Use of inhibitors or modulators of artemis in gene editing

Abstract

The present disclosure provides modulators or inhibitors of Artemis and their uses for promoting sequence integration into a target genomic locus in a cell by non-homologous end joining-mediated prime editing.

Description

[0001] Use of Inhibitors or Modulators of Artemis in Gene Editing FIELD OF THE INVENTION The present disclosure provides methods of inserting a polynucleotide of interest into the genome of a eukaryotic cell, wherein said methods comprise improving the efficiency of CRISPR / Cas-mediated polynucleotide insertion by addition of an inhibitor of the DNA nuclease Artemis to the eukaryotic cell. The present disclosure further provides compositions for inserting a polynucleotide of interest into the genome of a eukaryotic cell, and kits for inserting a gene of interest into the genome of a eukaryotic cell. BACKGROUND The development of cost-efficient and reliable methods for precise targeted alterations to the genome of living cells has been a long-standing goal. Genome editing has the potential to eliminate genes responsible for a particular disorder (i.e. a gene “knock-out”), or alternatively, provide a means for gene manipulation or insertion to correct a genetic deficiency or enhance a biological process via a gene “knock-in.” Genome editing can be applied for treatment of a multitude of disorders, including treatment of inherited disorders, hematological disorders and cancer, and in methods of immunotherapy. Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR- associated (Cas) systems are prokaryotic immune systems first discovered by Ishino in E. coli (Ishino et al., Journal of Bacteriology 169(12):5429-5433 (1987)). The prokaryotic immune system provides immunity against viruses and plasmids by targeting the nucleic acids of the viruses and plasmids in a sequence-specific manner. See also Soret et al., Nature Reviews Microbiology 6(3):181-186 (2008). Since its original discovery, multiple groups have performed extensive research around potential applications of the CRISPR system in genetic engineering, including gene editing (Jinek et al., Science 337(6096):816-821 (2012); Cong et al., Science 339(6121):819-823 (2013); and Mali et al., Science 339(6121):823-826 (2013)). The CRISPR-Cas9 gene editing system has been used successfully in a wide range of organisms and cell lines. In addition to genome editing, the CRISPR system has a multitude of other applications, including regulating gene expression, genetic circuit construction, and functional genomics, amongst others (reviewed in Sander et al., Nature Biotechnology 32:347-355 (2014)). Anzalone et al. (Nature 576: 149-157 (2019)) described the development of prime editing, which utilizes a programmable nickase, which generates a single-stranded break, fused to a reverse transcriptase, which can insert short sequences at the site of cleavage. In PRINS (Peterka et al., 2022), a variant of the Prime Editing genome editing technology, instead of a nickase-variant, a fully active SpCas9 nuclease is fused together with the M-MLV reverse transcriptase editor (PEn) and delivered to cells together with a modified 3’-extended sgRNA devoid of any homology arm (springRNA, Single PRimed INsertion gRNA)) which is then capable of inserting nucleotides at the site of cleavage through the Non- Homologous End Joining pathway. Several challenges remain with CRISPR technology and in particular Prime editing technology. A challenge with PRINS and similar methods of Prime Editing is to insert increasing larger sequences into the target genome while maintaining insertion precision. It is an object of the present invention to address this challenge. SUMMARY The present inventors have demonstrated that by inhibiting a protein known as Artemis, which is a 685 amino acid protein encoded by the DCLRE1C gene in humans (Moshous et al., 2001) (Gene ID: 64421) the efficiency and precision of Primed Insertion technology can be significantly improved. Accordingly, the inventors provide herein for the first time methods and composition to achieve efficient targeted insertions of long sequences into a target genome by inhibition of Artemis and / or the gene and the gene product of DCLRE1C. An aspect of the disclosure provides a modulator or inhibitor of Artemis for promoting sequence integration into a target genomic locus in a cell by non-homologous end joining- mediated prime editing. In some embodiments, the modulator or inhibitor may be used to increase the frequency of integration of a polynucleotide of interest into a target genomic locus in a cell by non- homologous end joining-mediated prime editing. In some embodiments, the modulator or inhibitor may be used to increase the integration of a polynucleotide of interest of at least 10 nucleotides in length into a target genomic locus in a cell by non-homologous end joining-mediated prime editing. In some embodiments, the inhibitor may be an Artemis dominant-negative embodiment or analogue of Artemis. In some embodiments, the dominant-negative embodiment or analogue of Artemis may be a polypeptide that has at least 90% sequence identity of SEQ ID NO:14. In some embodiments the dominant-negative embodiment or analogue of Artemis may be a polypeptide that has at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% sequence sequence identity of SEQ ID NO:14. Preferably, the dominant-negative embodiment or analogue of Artemis may be a polypeptide that has 100% sequence identity of SEQ ID NO:14 In some embodiments, the inhibitor may be a β-lactam antibiotic. In some embodiments, the inhibitor may be from a CRISPR-based gene silencing system. In some embodiments, the inhibitor may be an antisense oligonucleotide. In some embodiments, the antisense oligonucleotide may comprising a oligonucleotide sequence identical to any one of SEQ ID Nos: 57-118 or 119-173. In some embodiments, the inhibitor may be a RNAi molecule. In some embodiments, the modulator or inhibitor may reduce the expression of the Artemis-encoding gene (DCLRE1C) by at least 70%. In some embodiments, the modulator or inhibitor may reduce the expression of the Artemis-encoding gene (DCLRE1C) by at least 70%, by at least 71%, by at least 72%, by at least 73%, by at least 74%, by at least 75%, by at least 76%, by at least 77%, by at least 78%, by at least 79%, by at least 80%, by at least 81%, by at least 82%, by at least 83%, by at least 84%, by at least 85%, by at least 86%, by at least 87%, by at least 88%, by at least 89%, by at least 90%, by at least 91%, by at least 92%, by at least 93%, by at least 94%, by at least 95%, by at least 96%, by at least 97%, by at least 98%, by at least 99%. In some embodiments, the modulator or inhibitor may reduce the expression of the Artemis-encoding gene (DCLRE1C) by 100%. In some embodiments, the inhibitor may be a polypeptide comprising sequence SEQ ID NO:20. In some embodiments, the modulator or inhibitor of Artemis may be used to increase the efficiency of gene editing of cells. An aspect of the disclosure provides a method of integrating a polynucleotide of interest into a target genomic locus in a eukaryotic cell, the method comprising contacting a composition comprising the eukaryotic cell with an inhibitor or modulator of Artemis, adding a Cas nuclease to the composition, adding a reverse transcriptase or a DNA polymerase to the composition, adding the polynucleotide of interest to the composition, and adding a springRNA, wherein the polynucleotide of interest is inserted into the genome by non-homologous end joining. In some embodiments, the inhibitor or modulator of Artemis may be as defined above. In some embodiments, the Cas nuclease may be selected from Cas9, Cas12, or Cas14. In some embodiments, the Cas nuclease may be a fusion protein comprising a Cas nuclease and a reverse transcriptase or a DNA polymerase. In some embodiments, the method may further comprise adding a polynucleotide comprising an RNA guide sequence, a Cas-binding region, and a DNA template sequence, or combinations thereof. In some embodiments, the springRNA may comprise a primer-binding site, an RNA guide sequence, a Cas-binding region, and a DNA template sequence encoding the polynucleotide of interest. Preferably, the spring RNA is devoid of a homology arm (HA) that enables homology dependent repair into the genome. In some embodiments, the springRNA has a spacer sequence at the 5’end, wherein the spacer sequences specifically hybridizes to the target sequence. In some embodiments, the PBS is at the 3’end of the springRNA. In some embodiments, the polynucleotide of interest, the springRNA, and a polynucleotide encoding the Cas fusion protein may be encoded on a single vector. In some embodiments, the vector may be a viral vector. In some embodiments, the viral vector may be a retrovirus, a lentivirus, an adenovirus, or an adeno-associated virus. In some embodiments, the cell may be a mammalian cell. In some embodiments, the target genomic locus may be a gene of interest. In some embodiments, the Cas protein, the polynucleotide of interest, and springRNA may be delivered to the cell by microinjection, electroporation, a lipid nanoparticle, a liposome, an exosome, a gold nanoparticle, or a DNA nanoclew. In some embodiments, the polynucleotide of interest may comprise a gene of interest. In some embodiments, the polynucleotide of interest may be 1 to 50 base pairs in length. In some embodiments, the polynucleotide of interest may be double stranded with a 3′ overhang. In some embodiments, the polynucleotide of interest may be double stranded with a 5′ overhang. In some embodiments, the polynucleotide of interest encodes a protein tag. In some embodiments, the protein tag is selected from a fluorescent tag and an affinity tag. In some embodiments, the inhibitor or modulator of Artemis may be added to the composition from 0 minutes to about 48 hours before the Cas fusion protein is added to the composition. In some embodiments, the inhibitor may be added to cells at a concentration of about 1 mM to about 50 mM. In some embodiments, the inhibitor or modulator of Artemis may be administered at least once, at least twice, or at least three times. An aspect of the disclosure provides a method of gene editing a population of cells comprising contacting the population of cells with a modulator or inhibitor of Artemis and introducing non-homologous end joining-mediated prime editing machinery to the population of cells with one or more vectors, thereby editing the genome of the cells. In some embodiments, the inhibitor or modulator of Artemis may be as defined above. In some embodiments, the steps of contacting and introducing may be carried out ex vivo or in vitro. In some embodiments, the method may further comprise enriching the population of cells for cells that have been edited. An aspect of the disclosure provides a population of gene-edited cells prepared according to the above methods. An aspect of the disclosure provides a pharmaceutical composition comprising the population of gene-edited cells as described above. In some embodiments, the population of gene-edited cells or the pharmaceutical composition may be used in therapy. In some embodiments, the cells may be administered as part of an autologous stem cell transplant procedure or an allogeneic stem cell transplant procedure. An aspect of the disclosure provides a method for protein tagging of cells. An aspect of the disclosure provides a kit for combined, separate, or sequential use, comprising non-homologous end joining-mediated prime editing machinery and an inhibitor or a modulator of Artemis. An aspect of the disclosure provides an antisense oligonucleotide comprising a oligonucleotide sequences identical to any one of SEQ ID Nos: 57-118 or 119-173. Aspects and embodiments of the invention are set out in the appended claims. These and other aspects and embodiments of the invention are also described herein. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1. is a schematic representation of NHEJ-mediated Prime Editing (PRINS) for inserting DNA into the target region of the genome and how Artemis inhibition or deletion leads to increased insertion length. A A. This drawing depicts the homology-independent springRNA design. Each springRNA has at the 5’ end a spacer sequence specific to a target site, and the scaffold sequence recognize by the Cas9 enzyme. In the 3’ extension of each springRNA there is a primer binding site (PBS) for the reverse-transcriptase (RT) to initiate reverse transcription of the desired insert included after the PBS., The resulting 3’ overhang generated by the RT would require NHEJ activity to incorporate the insert into the genome. B. This drawing depicts the 4 steps of PRINS. Step 1: The Cas9-reverse transcriptase fusion enzyme binds to the modified sgRNA (springRNA), and causes a double stranded break at the location in the genome specified by the spacer sequence. Step 2: The reverse transcriptase fused to Cas9 synthesizes a DNA overhang from the template provided by the springRNA. Step 3: The cellular DNA repair factors re-ligates the double stranded break and fills-in the overhang into a double stranded DNA. Step 4: The double stranded break is fully repaired . CB. This drawing depicts how Artemis is involved in DNA repair during PRINS editing and how its inhibition or deletion improves the editing outcome. Artemis is recruited to the double stranded break by DNA-PK where it partially degrades the 3’ DNA overhang generated by PRINS editing. Removing or deleting Artemis leads to protection of the 3’ DNA overhang, increasing average insertion length of the overhang and increasing integration rate of the desired insert sequence. Figure 2. Shown are the results of DCLRE1C knockout on the length of PRINS-mediated insertions at the DPM2 target site in HAP1, HEK293T, and iPSC background. A. The graphs show the average insertion length at four different genomic target sites (DPM2, PCKS9, PDCD1, TRAC) in three cell background (HAP1, HEK293T, iPSCs) between WT and DCLRE1C knockout (DCLRE1C - / -) after PRINS editing with springRNA. Above each individual graph is the cell background, the target site, and the intended insertion length. The average insertion length in base pairs (bp) is on the Y-axis, and the genotype (WT or DCLRE1C- / -) is on the X-axis. The lines and symbols represent the average of two or three biological replicates with standard deviation included. B. This is the tabular results of the experiment above. Figure 3. Shown are the results of dominant negative Artemis mutant on the length of PRINS-mediated insertions at the DPM2 target site in a HEK293T background. A. The graphs show the average insertion length at four different genomic target sites (DPM2, PCKS9, PDCD1, TRAC) in HEK293T cells edited without (control) and with (Artemis D37N 1-413 a.a.) expression of a dominant negative mutant of Artemis after PRINS editing with springRNA. Above each individual graph is the cell background, the target site, and the intended insertion length. The average insertion length in base pairs (bp) is on the Y- axis, and the dominant negative mutant (control or Artemis D37N 1-413 a.a.) is on the X- axis. The lines and symbols represent the average of two biological replicates with standard deviation included. B. This is the tabular results of the experiment above. C. and D. The images shows representative images of the top editing outcome of the above described experiment in cells edited without and with the dominant negative mutant of Artemis. Each image list the sample names, the overall editing efficiency, the number of aligned reads, and a series of 10 editing outcomes (listed in different rows) aligned with the reference sequence above. Each row has the relative percentage of aligned reads (Ref. %), the overall percentage of aligned reads (Abs. %), the total number of aligned reads (Counts), and the length of the deletion or insertion of the indicated variant. Figure 4. Shown are the results of downregulation of DCLRE1C expression by siRNA on the length of PRINS-mediated insertions at the DPM2 target site in a HEK293T background. A. The graphs show the average insertion length at the genomic target site, DPM2, in HEK293T cells edited with either with a non-targeting siRNA pool or a DCLRE1C targeting siRNA pool after PRINS editing with springRNA. Above each individual graph is the cell background, the target site, and the intended insertion length. The average insertion length in base pairs (bp) is on the Y-axis, and the target of the siRNA pool is on the X-axis. The lines and symbols represent the average of two biological replicates with standard deviation included. B. This is the tabular results of the experiment above. Figure 5. Shown are the results of PRINS-mediated insertion of the Bxb1 attB 38bp sequence at three genomic target sites: A. AAVS1 (PPP1R12C), B. LDLR, and C. CFTR. The graphs show the integration efficiency of the attB sequence at the indicated target site after PRINS editing with springRNA in HEK293T cells. The integration efficiency in terms of the percentage of aligned reads containing the attB sequence is on the Y-axis, and the different springRNAs are on the X-axis. The white bars represent the average editing efficiency in the WT background and the black bar represent the average editing efficiency in the DCLRE1C background of three biological replicates with standard deviation included. Figure 6. Shown are the results of PRINS-mediated insertion with springRNA containing abasic site. The graph shows the levels of precise insertion or scaffold incorporated insertions at the DPM2 target site in HEK293T cells after PRINS editing with either unmodified springRNA or chemically modified springRNA with abasic site, called spaceRNA. The percentage or aligned reads that were either precise edits (black) or scaffold incorporated edits (gray) are on the Y-axis, and the type of springRNA used is on the X- axis. The bars compare the average editing outcomes between WT or DCLRE1C - / - background of three biological replicates with standard deviation included. Figure 7. Shown are the results of PRINS-mediated insertion of the FLAG tag sequence (30bp) at 5 different target sites: DMNT1, HEK3,RNF2, RUNX1, VEGFA. The graphs show the integration efficiency of the FLAG tag sequence at the indicated target site after PRINS editing with springRNA in HEK293T cells. The integration efficiency in terms of the percentage of aligned reads containing the FLAG tag sequence is on the Y-axis. The white bars represent the average editing efficiency in the WT background and the black bar represent the average editing efficiency in the DCLRE1C - / - background of three biological replicates with standard deviation included. Figure 8. Shown are the results of antisense oligonucleotide (ASOs)-mediated knockdown of human Artemis gene DCLRE1C in HEK293T cells. The graphs show the knockdown efficiency of DCLRE1C mRNA with ASOs targeting different regions of the gene. Relative gene expression, normalized to reference gene GAPDH, is on the Y-axis, and the different ASOs are on the X-axis. The bars represent the relative gene expression of a single biological replicates. Relative gene expression is compared with cells treated with a non- targeting ASO. Figure 9. Shown are the results of antisense oligonucleotide (ASOs)-mediated knockdown of mouse Artemis gene Dclre1c in AML-12 hepatocyte cells. The graphs show the knockdown efficiency of Dclre1c mRNA with ASOs targeting different regions of the gene. Relative gene expression, normalized to reference gene ACTB, is on the Y-axis, and the different ASOs are on the X-axis. The bars represent the relative gene expression of a single biological replicate. Relative gene expression is compared with cells treated with a non- targeting ASO. Figure 10. Shown are the results of knockdown of human Artemis gene DCLRE1C in HEK293T cells with three different modalities: CRISPRi promoter repression (dspCas9- KRAB-DNMT), siRNA, and ASOs. The graphs show the knockdown efficiency of DCLRE1C mRNA for each modality over a seven-day time course. Relative gene expression, normalized to reference gene GAPDH, is on the Y-axis, and the different modalities on the X-axis. The bars represent the relative gene expression compared with their appropriated control of a three biological replicate with standard deviation included. NT is the non-targeting sgRNA, non-targeting siRNA, or non-targeting ASOs for each of the three modalities, respectively. Figure 11. Shown are the results of PRINS-mediated insertion following CRISPRi mediated knockdown of Artemis at three genomic target sites (AAVS1 (PPP1R12C), DPM2, and PCSK9) in four different cell lines (K562, HEK293T, HeLa, HepG2). The graphs show the integration efficiency of the attB sequence at the indicated target site after PRINS editing with springRNA in HEK293T cells. The percentage or aligned reads that were either precise edits (black) or scaffold incorporated edits (gray) are on the Y-axis, and the type of sgRNA used for CRISPRi mediated knockdown is on the X-axis. The bars compare the average editing outcomes between CRISPRi knockdown with non-targeting sgRNA (NT) or DCLRE1C targeting sgRNA (DCLRE1C) of three biological replicates with standard deviation included. Figure 12. Shown are the results of PRINS-mediated insertion following ASOs-mediated knockdown of Artemis at three genomic target sites (AAVS1 (PPP1R12C), DPM2, and PCSK9) in HEK293T cells. The graphs show the integration efficiency of the attB sequence at the indicated target site after PRINS editing with springRNA in HEK293T cells. The percentage or aligned reads that were either precise edits (black) or scaffold incorporated edits (gray) are on the Y-axis, and the type of ASOs used is on the X-axis. The bars compare the average editing outcomes between non-targeting ASO (NT) or DCLRE1C targeting ASO (DCLRE1C) of three biological replicates with standard deviation included. Figure 13. Shown are the results of PRINS-mediated insertion of four different epitopes (His-tag, FLAG-tag, Myc-tag, and HIBIT-tag) following ASOs-mediated knockdown of Artemis on the MIF1 gene in HEK293T cells. The top graphs show the integration efficiency of each protein tags after PRINS editing with springRNA in HEK293T cells. The percentage of aligned reads that have the intended insertion are on the Y-axis, and the type of ASOs used is on the X-axis. The bars compare the average editing outcomes between non-targeting ASO (NT) or DCLRE1C targeting ASO (DCLRE1C) of three biological replicates with standard deviation included. The middle graph show the protein levels of correctly-tagged MIF1 protein by Western blot using appropriate antibodies. The bottom single graph show the HIBIT activity levels in the lysates of HEK293T using the HIBIT lytic assay. Figure 14. Shown are the results of PRINS-mediated insertion of different recombinase recognition sites (Bxb1 attB site, Cre loxP or lox71 site) following ASOs-mediated knockdown of Artemis. The left graphs show the integration efficiency of attB site insertion into the LDLR locus after PRINS editing with springRNA in HepG2 LDLR knockout cells. The right graph show the integration efficiency of loxP or lox71 site insertion into the DMD locus after PRINS editing with springRNA in HEK293T cells. The percentage or aligned reads that were either precise edits (black) or scaffold incorporated edits (gray) are on the Y-axis, and the type of ASOs used is on the X-axis. The bars compare the average editing outcomes between non-targeting ASO (NT) or DCLRE1C targeting ASO (DCLRE1C) of (HepG2-LDLR) three biological replicates with standard deviation included or (HEK293T- DMD) one biological replicate. DETAILED DESCRIPTION The present disclosure relates to methods of improving CRISPR / Cas-mediated gene insertion (i.e. gene “knock-in”) in eukaryotic cells, compositions for improved CRISPR / Cas-mediated insertion, and kits for improved CRISPR / Cas-mediated gene insertion. In general a CRISPR system, e.g., a CRISPR / Cas system, includes elements that promote the formation of a CRISPR complex, such as a guide polynucleotide and a Cas protein, at the site of a target polynucleotide, e.g., a target DNA sequence. In naturally- occurring CRISPR systems (e.g., the bacterial immunity CRISPR / Cas9 system), foreign DNA is incorporated into CRISPR arrays, which then produce CRISPR-RNAs (crRNA). The crRNA includes RNA guide sequence regions complementary to the foreign DNA site and hybridizes with trans-activating CRISPR-RNA (tracrRNA), which is also encoded by the CRISPR system. The tracrRNA forms secondary structures, e.g., stem loops, and is capable of binding to Cas9 protein. The crRNA / tracrRNA hybrid associates with Cas9, and the crRNA / tracrRNA / Cas9 complex recognizes and cleaves foreign DNA bearing the protospacer sequences, thereby conferring immunity against the invading virus or plasmid. CRISPR / Cas systems are further described in, e.g., Jinek et al., Science 337(6096):816-821 (2012); Cong et al., Science 339(6121):819-823 (2013); Mali et al., Science 339(6121):823-826 (2013); and Sander et al., Nat Biotechnol 32:347-355 (2014). The present disclosure relates to an improvement of PRINS. PRINS (PRimed INSertions) is an improvement of the Prime Editing genome editing technology - a technique that combines the gene targeting ability of Cas9 with the polymerase activity of a reverse transcriptase to introduce modifications into the human genome at specific target sites. PRINS comprises an active SpCas9 nuclease fused together with a reverse transcriptase editor (PEn) and delivered to cells together with a modified 3’-extended sgRNA (springRNA, Single PRimed INsertion gRNA) as described in WO2022214522A2. The extension on the sgRNA encodes a primer binding site and an RNA template to be synthesized into DNA. This RT template encodes the desired edit for introduction into the genome. The PEn editor generates a 3’-DNA overhang based on the RT template of the springRNA and the non-homologous end joining (NHEJ) repair factors will repair the double-stranded break. This repair mechanism will involve resecting and filling-in of the 3’-DNA overhang together with a ligation step resulting in the integration of the desired edit. By using the modulation or inhibition of Artemis to achieve the desired editing outcome, PRINS is an alternative means of editing the cells compared to the homology- driven repair mechanism that Prime Editing techniques use. In particular the present disclosure relates to an improvement in the efficiency of Prime Editing genome editing technology like PRINS by increasing the editing efficiency and editing precision of the technology. In other words, the present disclosure enables the provision of methods which results in more efficient and more precise insertion of nucleotide sequences into a target sequence. The inventors of the present invention have shown that the inhibition of Artemis expression or activity leads not only to an increase in the length of inserted sequence but also reduces the occurrence of errors in the inserted sequences. Artemis is a NHEJ-specific nuclease enzyme recruited to double-stranded breaks (DSBs) by DNA-PKcs. Artemis is a 685 amino acid protein encoded by the DCLRE1C gene in humans (Moshous et al., 2001 ) (Gene ID: 64421). In one embodiment the nucleotide sequence of the DCLRE1C gene comprises SEQ ID NO:1. In one embodiment the amino acid sequence of the Artemis protein comprises SEQ ID NO:4. Knocking out the DCLRE1C gene or inhibiting in other ways the Artemis activity reduces the amount of unintended indels resulting from PEn / springRNA editing. By removing Artemis or reducing Artemis activity, 3’ overhangs introduced by PRINS editing on the ends of a DSB is stabilized and more favorably integrated into the genome by ligation. A modulator or inhibitor of Artemis reduces the activity of the Artemis protein in the cell, including the expression of the polypeptide encoded by the DCLRE1C gene. As used herein, Artemis activity refers to the nucleolytic functions of the Artemis polypeptide associated with DNA end processing during non-homologous end joining (NHEJ) and related DNA repair pathways. In the context of the present disclosure, Artemis exhibits endonuclease and exonuclease activities that are activated and / or modulated by protein cofactors, including DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and are operative on structured DNA ends such as hairpins, overhangs, and single-stranded regions arising during V(D)J recombination or double-strand break repair. It is known in the art that phosphorylation of Artemis by DNA-PKcs can regulate its catalytic profile and substrate specificity. Artemis activity can be defined and quantified using in vitro and cell-based assays employing defined DNA substrates and readouts of end processing. For example, DNA hairpin substrates bearing radiolabels or fluorescent reporters are incubated with Artemis under nuclease assay conditions, and cleavage at the hairpin loop or near the apex is measured by fragment analysis, capillary electrophoresis, or denaturing gel electrophoresis. In another embodiment, synthetic double-stranded DNA substrates with predetermined 3′ or 5′ overhangs or blunt ends are used to assess Artemis endonuclease activity by monitoring conversion to processed products, including trimming of overhangs or creation of ligation-competent ends. In another example, single-stranded DNA substrates are provided to evaluate ssDNA-directed cleavage or limited exonucleolytic trimming, with product formation quantified by gel- or chromatography-based methods. Kinase-dependent regulation of Artemis is characterized by combining Artemis with DNA- PKcs and ATP in in vitro kinase assays, followed by nuclease measurements on matched DNA substrates to determine phosphorylation-dependent changes in activity, kinetics, or site selectivity. For example, cell-based recombination reporter substrates are integrated into cultured cells to assess Artemis-dependent end joining, wherein restoration of a reporter signal (or its modulation) is quantified after induction of site-specific DNA breaks and correlated with Artemis expression or perturbation. In certain implementations, cells deficient in Artemis or complemented with variant forms are used to attribute observed repair phenotypes to Artemis function. For the purposes of the present disclosure, Artemis activity encompasses measurable cleavage, trimming, or opening of DNA hairpins and structured DNA ends under defined reaction conditions, including buffer composition, divalent cation concentration, and presence or absence of regulatory cofactors. Activity is reported using quantitative metrics such as initial rate, turnover number, fraction substrate converted, or apparent catalytic efficiency, and may be normalized to enzyme amount or cellular expression levels. These definitions provide operational criteria to evaluate Artemis function and its modulation by inhibitor and modulators of Artemis including compounds, mutations, or binding partners in biochemical and cellular contexts relevant to maintenance of genomic integrity. As used herein, and unless otherwise specified, the term "knock-out," when used in connection with Artemis / DCLRE1C, means that the expression of Artemis / DCLRE1C is entirely or almost entirely abolished. The expression of Artemis / DCLRE1C that is knocked-out in a cell or a tissue can be reduced by at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, compared to its normal expression level in the cell or tissue. In some embodiments, the expression level of Artemis / DCLRE1C that is knocked-out in a cell is non-detectable using ordinary means known in the art for gene expression detection. As used herein, and unless otherwise specified, the term "knock-down," when used in connection with Artemis / DCLRE1C, means that the expression of the gene is significantly diminished. The expression of the indicated gene that is knocked-down in a cell or a tissue is reduced by at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%, compared to its normal expression level in the cell or the tissue. In some embodiments, the expression level of Artemis / DCLRE1C that is knocked-down in a cell or a tissue is reduced by at least 50% compared to the normal expression level of Artemis / DCLRE1C in the cell or tissue. In some embodiments, the knock-down is by antisense nucleotides, siRNAs, shRNAs or ribozymes that complementarily bind to the mRNA of the DCLRE1C gene. As used herein, a "dominant negative mutant" of Artemis / DCLRE1C a gene product of DCLRE1C or a Artemis protein that interferes with the function of a gene product of DCLRE1C or an Artemis protein. The dominant negative mutant can have many forms, including truncated, full-length proteins with point mutations or fragments thereof, or fusions of full length wild type or mutant proteins or fragments thereof with proteins other than Artemis. The level of inhibition observed can be very low. For example, it may require a large excess of dominant negative mutant to be involved in the process to observe effects compared to one or more functional proteins. In one embodiment the dominant negative mutant is comprises a protein according SEQ ID NO: 4 with one or more amino acid mutations. In one embodiment the dominant negative mutant can be a protein encoded by any one of SEQ ID Nos: SEQ ID: 7, SEQ ID: 10 SEQ ID: 13 and SEQ ID: 16. In some embodiments, the present disclosure provides compositions, polynucleotides, and / or Cas fusion proteins for improved targeted insertion methods. In some embodiments, the compositions, polynucleotides, and / or Cas fusion proteins of the present disclosure provide higher precision of inserting a sequence of interest. In some embodiments, the compositions, polynucleotides, and Cas fusion proteins of the present disclosure provide higher efficiency of inserting a sequence of interest. Unless otherwise defined herein, scientific and technical terms used in the present disclosure shall have the meanings that are commonly understood by one of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. As used herein, “a” or “an” may mean one or more. As used herein, when used in conjunction with the word “comprising,” the words “a” or “an” may mean one or more than one. As used herein, “another” or “a further” may mean at least a second or more. Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the method / device being employed to determine the value, or the variation that exists among the study subjects. Typically, the term “about” is meant to encompass approximately or less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% variability, depending on the situation. The use of the term “or” in the claims is used to mean “and / or”, unless explicitly indicated to refer only to alternatives or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and / or.” As used herein, the terms “comprising” (and any variant or form of comprising, such as “comprise” and “comprises”), “having” (and any variant or form of having, such as “have” and “has”), “including” (and any variant or form of including, such as “includes” and “include”) or “containing” (and any variant or form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited, elements or method steps. It is contemplated that any embodiment discussed in this specification can be implemented with respect to any protein, compositions, polynucleotides, vectors, cells, methods, and / or kits of the present disclosure. Furthermore, compositions, polynucleotides, vectors, cells, and / or kits of the present disclosure can be used to achieve methods and proteins of the present disclosure. The use of the term “for example” and its corresponding abbreviation “e.g.” (whether italicized or not) means that the specific terms recited are representative examples and embodiments of the disclosure that are not intended to be limited to the specific examples referenced or cited unless explicitly stated otherwise. As used herein, “between” is a range inclusive of the ends of the range. For example, a number between x and y explicitly includes the numbers x and y, and any numbers that fall within x and y. A “nucleic acid,” “nucleic acid molecule,” “nucleotide,” “nucleotide sequence,” “oligonucleotide,” or “polynucleotide” means a polymeric compound including covalently linked nucleotides. The term “nucleic acid” includes ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) both of which may be single- or double-stranded. The polynucleotide may comprise naturally-occurring nucleobases (e.g., guanine, adenine, cytosine, thymine, and uracil), modified nucleobases (e.g., hypoxanthine, xanthine, 7- methylguanine, dihydrouracil, 5-methylcytosine, 5-hydroxymethylcytosine), and / or artificial nucleobases (e.g., isoguanine or isocytosine). Nucleic acids are transcribed from a 5’ end to a 3’ end. In some embodiments, the disclosure provides a polynucleotide comprising RNA and DNA nucleotides. Methods of producing a polynucleotide comprising both RNA and DNA nucleotides are known in the art and include, e.g., ligation or oligonucleotide synthesis methods. In some embodiments, the disclosure provides a polynucleotide capable of forming a complex with a Cas nuclease as described herein. In some embodiments, the disclosure provides a polynucleotide encoding any one of the proteins disclosed herein, e.g., a Cas nuclease. A “gene” refers to an assembly of nucleotides that encode a polypeptide and includes cDNA and genomic DNA nucleic acid molecules. In some embodiments, “gene” also refers to a non-coding nucleic acid fragment that can act as a regulatory sequence preceding (i.e., 5’) and following (i.e., 3’) the coding sequence. A nucleic acid molecule is “hybridizable” or “hybridized” to another nucleic acid molecule, such as a cDNA, genomic DNA, or RNA, when a single stranded form of the nucleic acid molecule can anneal to the other nucleic acid molecule under the appropriate conditions of temperature and solution ionic strength. Hybridization and washing conditions are known and exemplified in Sambrook et al., Molecular Cloning: A Laboratory Manual, Second Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor (1989), particularly Chapter 11 and Table 11.1 therein. The conditions of temperature and ionic strength determine the stringency of the hybridization. The stringency of the hybridization conditions can be selected to provide selective formation or maintenance of a desired hybridization product of two complementary polynucleotides, in the presence of other potentially cross-reacting or interfering polynucleotides. Stringent conditions are sequence- dependent; typically, longer complementary sequences specifically hybridize at higher temperatures than shorter complementary sequences. Generally, stringent hybridization conditions are between about 5 °C to about 10 °C lower than the thermal melting point (Tm) (i.e., the temperature at which 50% of the sequences hybridize to a substantially complementary sequence) for a specific polynucleotide at a defined ionic strength, concentration of chemical denaturants, pH, and concentration of the hybridization partners. Generally, nucleotide sequences having a higher percentage of G and C bases hybridize under more stringent conditions than nucleotide sequences having a lower percentage of G and C bases. Generally, stringency can be increased by increasing temperature, increasing pH, decreasing ionic strength, and / or increasing the concentration of chemical nucleic acid denaturants (such as formamide, dimethylformamide, dimethylsulfoxide, ethylene glycol, propylene glycol and ethylene carbonate). Stringent hybridization conditions typically include salt concentrations or ionic strength of less than about 1 M, 500 mM, 200 mM, 100 mM or 50 mM; hybridization temperatures above about 20 °C, 30 °C, 40 °C, 60 °C or 80 °C; and chemical denaturant concentrations above about 10%, 20%, 30% 40% or 50%. Because many factors can affect the stringency of hybridization, the combination of parameters may be more significant than the absolute value of any parameter alone. The term “complementary” is used to describe the relationship between nucleotide bases that are capable of hybridizing to one another. For example, with respect to DNA, adenosine is complementary to thymine and cytosine is complementary to guanine. When two nucleic acids are “complementary,” it is meant that a first nucleic acid or one or more regions thereof is capable of hydrogen bonding with a second nucleic acid or one or more regions thereof. Complementary nucleic acids need not have complementarity at each nucleotide and may include one or more nucleotide mismatches, i.e., points at which hydrogen bonding does not occur. For example, complementary oligonucleotides can have at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of nucleotides hydrogen bond. By contrast, "fully complementary" or "100% complementary" in reference to oligonucleotides means that each nucleotide hydrogen bonds without any nucleotide mismatches. The term “homologous recombination” refers to the insertion of an exogenous polynucleotide (e.g., DNA) into another nucleic acid (e.g., DNA) molecule, e.g., insertion of a vector, polynucleotide fragment or gene in a chromosome. In some cases, the exogenous polynucleotide targets a specific chromosomal site for homologous recombination. For specific homologous recombination, the exogenous polynucleotide typically contains sufficiently long regions of homology to sequences of the chromosome to allow complementary binding and incorporation of the exogenous polynucleotide into the chromosome. Longer regions of homology and greater degrees of sequence similarity may increase the efficiency of homologous recombination. In some embodiments, the polynucleotides or compositions described herein facilitate homologous recombination by generating breaks, e.g., double-stranded breaks in a nucleic acid sequence. The term “homology-directed repair” or “HDR” refers to a mechanism of repairing double- stranded breaks in DNA using a template nucleic acid sequence. The most common form of HDR is homologous recombination. In HDR, a double-stranded break is repaired by a process involving resection of the 5’ ended DNA strand at the break to create a 3’ overhang, which serves as both a substrate for proteins required for strand invasion and as a primer for DNA repair synthesis. The invasive strand then displaces one strand of a double- stranded DNA template sequence which comprises homologous sequences and pair with the other strand, resulting in the formation of hybrid DNA known as the displacement loop. These recombination intermediates are then resolved to complete the DNA repair process. The term “non-homologous end joining pathway” or “NHEJ pathway” refers to another mechanism of repairing double-stranded breaks in DNA. In NHEJ, a Ku80 / 70 heterodimer recognizes and binds to blunt ends formed by the double-stranded break, where the resulting complex activates the activity of DNA-PK. Activation of DNA-PK recruits Artemis nuclease, DNA polymerases, and DNA ligases to ultimately repair the double- stranded break. NHEJ differs from HDR and homologous recombination that that it does not require a homologous template sequence for repair. As used herein, the term “operably linked” means that a polynucleotide of interest, e.g., the polynucleotide encoding a nuclease, is linked to the regulatory element in a manner that allows for expression of the polynucleotide. Regulatory elements can be cis-regulatory elements or trans-regulatory elements. Regulatory elements include, for example, promoters, enhancers, terminators, 5’ and 3’ UTRs, insulators, silencers, operators, and the like. In some embodiments, the regulatory element is a promoter. In some embodiments, a polynucleotide expressing a protein of interest is operably linked to a promoter on an expression vector. A “vector” is any means for the cloning of and / or transfer of a nucleic acid into a host cell. A vector may be a replicon to which another DNA segment may be attached so as to bring about the replication of the attached segment. A “replicon” is any genetic element (e.g., plasmid, phage, cosmid, chromosome, virus) that functions as an autonomous unit of DNA replication in vivo, i.e., capable of replication under its own control. In some embodiments, the vector is an episomal vector, which is removed / lost from a population of cells after a number of cellular generations, e.g., by asymmetric partitioning. The term “vector” includes both viral and non-viral means for introducing the nucleic acid into a cell in vitro, ex vivo, or in vivo. A large number of vectors known in the art may be used to manipulate nucleic acids, incorporate response elements and promoters into genes, etc. A vector may include one or more regulatory regions, and / or selectable markers useful in selecting, measuring, and monitoring nucleic acid transfer results (transfer to which tissues, duration of expression, etc.). Possible vectors include, for example, plasmids or modified viruses including, for example, bacteriophages such as lambda derivatives, or plasmids such as PBR322 or pUC plasmid derivatives, or the Bluescript vector. For example, the insertion of the DNA fragments corresponding to response elements and promoters into a suitable vector can be accomplished by ligating the appropriate DNA fragments into a chosen vector that has complementary cohesive termini. Alternatively, the ends of the DNA molecules may be enzymatically modified, or any site may be produced by ligating polynucleotides (linkers) into the DNA termini. Such vectors may be engineered to contain selectable marker genes that provide for the selection of cells that have incorporated the marker into the cellular genome. Such markers allow identification and / or selection of host cells that incorporate and express the proteins encoded by the marker. Viral vectors, and particularly retroviral vectors, have been used in a wide variety of gene delivery applications in cells, as well as living animal subjects. Viral vectors that can be used include, but are not limited, to retrovirus, lentivirus, adenovirus, adeno-associated virus, pox, baculovirus, vaccinia, herpes simplex, Epstein-Barr, adenovirus, geminivirus, and caulimovirus vectors. In some embodiments, a viral vector is utilized to provide the polynucleotides described herein. In some embodiments, a viral vector is utilized to provide a polynucleotide coding for a protein described herein. Vectors may be introduced into the desired host cells by known methods, including, but not limited to, transfection, transduction, cell fusion, and lipofection. Vectors can include various regulatory elements including promoters. In some embodiments, vector designs can be based on constructs designed by Mali et al., Nat Methods 10: 957-63 (2013). Methods known in the art may be used to propagate polynucleotides and / or vectors provided herein. Once a suitable host system and growth conditions are established, recombinant expression vectors can be propagated and prepared in quantity. As described herein, the expression vectors which can be used include, but are not limited to, the following vectors or their derivatives: human or animal viruses such as vaccinia virus or adenovirus; insect viruses such as baculovirus; yeast vectors; bacteriophage vectors (e.g., lambda), and plasmid and cosmid DNA vectors. The term “plasmid” refers to an extra chromosomal element often carrying a gene that is not part of the central metabolism of the cell, and usually in the form of circular double- stranded DNA molecules. Such elements may be autonomously replicating sequences, genome integrating sequences, phage or nucleotide sequences, linear, circular, or supercoiled, of a single- or double-stranded DNA or RNA, derived from any source, in which a number of polynucleotides have been joined or recombined into a unique construction which is capable of introducing a promoter fragment and DNA sequence for a selected gene product along with appropriate 3’ untranslated sequence into a cell. In some embodiments, a plasmid is utilized to provide the polynucleotides described herein. In some embodiments, a plasmid is utilized to provide a polynucleotide coding for a protein described herein. The term “transfection” as used herein means the introduction of an exogenous nucleic acid molecule, including a vector, into a cell. Transfection methods, e.g., for components of the CRISPR / Cas compositions described herein, are known to one of ordinary skill in the art. A “transfected” cell includes an exogenous nucleic acid molecule inside the cell and a “transformed” cell is one in which the exogenous nucleic acid molecule within the cell induces a phenotypic change in the cell. The transfected nucleic acid molecule can be integrated into the host cell’s genomic DNA and / or can be maintained by the cell, temporarily or for a prolonged period of time, extra-chromosomally. Host cells or organisms that express exogenous nucleic acid molecules or fragments are referred to herein as “recombinant,” “transformed,” or “transgenic” organisms. In some embodiments, the present disclosure provides a host cell comprising any of the vectors described herein, e.g., a vector comprising a Cas polynucleotide, a vector comprising the polynucleotide of interest, or a vector comprising a polynucleotide comprising an RNA guide sequence, a CAS-binding region, a DNA Template sequence or combinations thereof. The term “host cell” refers to a cell into which a recombinant expression vector has been introduced, or “host cell” may also refer to the progeny of such a cell. Because modifications may occur in succeeding generations, for example, due to mutation or environmental influences, the progeny may not be identical to the parent cell, but are still included within the scope of the term “host cell.” The terms “peptide,” “polypeptide,” and “protein” are used interchangeably herein, and refer to a polymeric form of amino acids of any length, which can include coded and non- coded amino acids, non-naturally occurring amino acids, chemically or biochemically modified or derivatized amino acids, peptides and polypeptides having modified peptide backbones, and circular / cyclic peptides and polypeptides. The start of the protein or polypeptide is known as the “N-terminus” (and also referred to as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus), referring to the free amine (-NH2) group of the first amino acid residue of the protein or polypeptide. The end of the protein or polypeptide is known as the “C-terminus” (and also referred to as the carboxy-terminus, carboxyl-terminus, C-terminal end, or COOH-terminus), referring to the free carboxyl group (-COOH) of the last amino acid residue of the protein or polypeptide. An “amino acid” as used herein refers to a compound including both a carboxyl (-COOH) and amino (-NH2) group. “Amino acid” refers to both natural and unnatural, i.e., synthetic, amino acids. Natural amino acids, with their three-letter and single-letter abbreviations, include: alanine (Ala; A); arginine (Arg, R); asparagine (Asn; N); aspartic acid (Asp; D); cysteine (Cys; C); glutamine (Gln; Q); glutamic acid (Glu; E ); glycine (Gly; G); histidine (His; H); isoleucine (Ile; I); leucine (Leu; L); lysine (Lys; K); methionine (Met; M); phenylalanine (Phe; F); proline (Pro; P); serine (Ser; S); threonine (Thr; T); tryptophan (Trp; W); tyrosine (Tyr; Y); and valine (Val; V). Unnatural or synthetic amino acids include a side chain that is distinct from the natural amino acids provided above and may include, e.g., fluorophores, post-translational modifications, metal ion chelators, photocaged and photocross-linking moieties, uniquely reactive functional groups, and NMR, IR, and x-ray crystallographic probes. Exemplary unnatural or synthetic amino acids are provided in, e.g., Mitra et al., Mater Methods 3:204 (2013) and Wals et al., Front Chem 2:15 (2014). Unnatural amino acids may also include naturally-occurring compounds that are not typically incorporated into a protein or polypeptide, such as, e.g., citrulline (Cit), selenocysteine (Sec), and pyrrolysine (Pyl). An “amino acid substitution” refers to a polypeptide or protein including one or more substitutions of wild-type or naturally occurring amino acid with a different amino acid relative to the wild-type or naturally occurring amino acid at that amino acid residue. The substituted amino acid may be a synthetic or naturally occurring amino acid. In some embodiments, the substituted amino acid is a naturally occurring amino acid selected from the group consisting of: A, R, N, D, C, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y, and V. In some embodiments, the substituted amino acid is an unnaturally or synthetic amino acid. Substitution mutants may be described using an abbreviated system. For example, a substitution mutation in which the fifth (5th) amino acid residue is substituted may be abbreviated as “X5Y,” wherein “X” is the wild-type or naturally occurring amino acid to be replaced, “5” is the amino acid residue position within the amino acid sequence of the protein or polypeptide, and “Y” is the substituted, or non-wild-type or non-naturally occurring, amino acid. An “isolated” polypeptide, protein, peptide, or nucleic acid is a molecule that has been removed from its natural environment. It is also understood that “isolated” polypeptides, proteins, peptides, or nucleic acids may be formulated with excipients such as diluents or adjuvants and still be considered isolated. As used herein, “isolated” does not necessarily imply any particular level purity of the polypeptide, protein, peptide, or nucleic acid. The term “recombinant” when used in reference to a nucleic acid molecule, peptide, polypeptide, or protein means of, or resulting from, a new combination of genetic material that is not known to exist in nature. A recombinant molecule can be produced by any of the techniques available in the field of recombinant technology, including, but not limited to, polymerase chain reaction (PCR), gene splicing (e.g., using restriction endonucleases), and solid-phase synthesis of nucleic acid molecules, peptides, or proteins. The term “exogenous” means that the referenced molecule or activity introduced into the host cell. The molecule can be introduced, for example, by introduction of an encoding nucleic acid into the host genetic material, such as by integration into a host chromosome or as non-chromosomal genetic material, e.g., a plasmid. An “exogenous” protein can be introduced into a host cell via an “exogenous” nucleic acid encoding the protein. The term “endogenous” refers to a referenced molecule or activity that is naturally present in the host cell. An “endogenous” protein is expressed by a nucleic acid contained within the host cell. The term “heterologous” refers to a molecule or activity derived from a source other than the referenced organism / species, whereas “homologous” refers to a molecule or activity derived from the host organism / species. Accordingly, exogenous expression of an encoding nucleic acid can utilize either or both of a heterologous or homologous encoding nucleic acid. The term “domain” when used in reference to a polypeptide or protein means a distinct functional and / or structural unit in a protein. Domains are sometimes responsible for a particular function or interaction, contributing to the overall role of a protein. Domains may exist in a variety of biological contexts. Similar domains may be found in proteins with different functions. Alternatively, domains with low sequence identity (i.e., less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 5%, or less than about 1% sequence identity) may have the same function. The term “motif,” when used in reference to a polypeptide or protein, generally refers to a set of conserved amino acid residues, typically shorter than 20 amino acids in length, that may be important for protein function. Specific sequence motifs may mediate a common function, such as protein-binding or targeting to a particular subcellular location, in a variety of proteins. Examples of motifs include, but are not limited to, nuclear localization signals, microbody targeting motifs, motifs that prevent or facilitate secretion, and motifs that facilitate protein recognition and binding. Motif databases and / or motif searching tools are known in the field and include, for example, PROSITE, PFAM, PRINTS, and MiniMotif Miner. An “engineered” protein, as used herein, means a protein that includes one or more modifications in a protein to achieve a desired property. Exemplary modifications include, but are not limited to, insertion, deletion, substitution, and / or fusion with another domain or protein. A “fusion protein” (also termed “chimeric protein”) is a protein comprising at least two domains, typically coded by two separate genes, that have been joined such that they are transcribed and translated as a single unit, thereby producing a single polypeptide having the functional properties of each of the domains. Engineered proteins of the present disclosure include Cas nucleases, Cas nickases, and fusions of Cas proteins with a DNA polymerase, DNA ligase, and / or DNA polymerase-binding protein. In some embodiments, engineered protein is generated from a wild-type protein. As used herein, a “wild-type” protein or nucleic acid is a naturally-occurring, unmodified protein or nucleic acid. For example, a wild-type Cas9 protein can be isolated from the organism Streptococcus pyogenes. Wild-type can be contrasted with “mutant,” which includes one or more modifications in the amino acid and / or nucleotide sequence of the protein or nucleic acid. In some embodiments, an engineered protein can have substantially the same activity as a wild-type protein, e.g., greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, or greater than about 99% of the activity as a wild- type protein. In some embodiments, the Cas nuclease of a Cas fusion protein described herein has substantially the same activity as a wild-type Cas nuclease. In some embodiments, an engineered protein, e.g., a Cas9 protein, can have substantially the same amino acid sequence as a wild-type protein, e.g., greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, or greater than about 99% identify as a wild-type protein. As used herein, the terms “sequence similarity” or “% similarity” refers to the degree of identity or correspondence between nucleic acid sequences or amino acid sequences. In the context of polynucleotides, “sequence similarity” may refer to nucleic acid sequences where changes in one or more nucleotide bases results in substitution of one or more amino acids, but do not affect the functional properties of the protein encoded by the polynucleotide. “Sequence similarity” may also refer to modifications of the polynucleotide, such as deletion or insertion of one or more nucleotide bases, that do not substantially affect the functional properties of the resulting transcript. It is therefore understood that the present disclosure encompasses more than the specific exemplary sequences. Methods of making nucleotide base substitutions are known, as are methods of determining the retention of biological activity of the encoded polypeptide. Moreover, the skilled artisan recognizes that similar polynucleotides encompassed by the present disclosure are also defined by their ability to hybridize, under stringent conditions, with the sequences exemplified herein. Similar polynucleotides of the present disclosure are about 70%, at least about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 90%, at least about 90%, about 95%, at least about 95%, about 99%, at least about 99%, or about 100% identical to the polynucleotides disclosed herein. In the context of polypeptides, “sequence similarity” refers to two or more polypeptides where greater than about 40% of the amino acids are identical, or greater than about 60% of the amino acids are functionally identical. “Functionally identical” or “functionally similar” amino acids have chemically similar side chains. For example, amino acids can be grouped in the following manner according to functional similarity: (i) positively-charged side chains: Arg, His, Lys; (ii) negatively-charged side chains: Asp, Glu; (iii) polar, uncharged side chains: Ser, Thr, Asn, Gln; (iv) hydrophobic side chains: Ala, Val, Ile, Leu, Met, Phe, Tyr, Trp; and (v) others: Cys, Gly, Pro. In some embodiments, similar polypeptides of the present disclosure have about 40%, at least about 40%, about 45%, at least about 45%, about 50%, at least about 50%, about 55%, at least about 55%, about 60%, at least about 60%, about 65%, at least about 65%, about 70%, at least about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 90%, at least about 90%, about 95%, at least about 95%, about 97%, at least about 97%, about 98%, at least about 98%, about 99%, at least about 99%, or about 100% identical amino acids. In some embodiments, similar polypeptides of the present disclosure have about 60%, at least about 60%, about 65%, at least about 65%, about 70%, at least about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 90%, at least about 90%, about 95%, at least about 95%, about 97%, at least about 97%, about 98%, at least about 98%, about 99%, at least about 99%, or about 100% functionally identical amino acids. Sequence similarity can be determined by sequence alignment using methods known in the field, such as, for example, BLAST, MUSCLE, Clustal (including ClustalW and ClustalX), and T-Coffee (including variants such as, for example, M-Coffee, R-Coffee, and Expresso). Percent identity of polynucleotides or polypeptides can be determined when the polynucleotide or polypeptide sequences are aligned over a specified comparison window. In some embodiments, only specific portions of two or more sequences are aligned to determine sequence identity. In some embodiments, only specific domains of two or more sequences are aligned to determine sequence similarity. A comparison window can be a segment of at least 10 to over 1000 residues, at least 20 to about 1000 residues, or at least 50 to 500 residues in which the sequences can be aligned and compared. Methods of alignment for determination of sequence identity are well-known and can be performed using publicly available databases such as BLAST. For example, in some embodiments, “percent identity” of two amino acid sequences is determined using the algorithm of Karlin and Altschul, Proc Nat Acad Sci USA 87:2264-2268 (1990), modified as in Karlin and Altschul, Proc Nat Acad Sci USA 90:5873-5877 (1993). Such algorithms are incorporated into BLAST programs, e.g., BLAST+ or the NBLAST and XBLAST programs described in Altschul et al., J Mol Biol, 215: 403-410 (1990). BLAST protein searches can be performed with programs such as, e.g., the XBLAST program, score=50, wordlength=3 to obtain amino acid sequences homologous to the protein molecules of the disclosure. Where gaps exist between two sequences, Gapped BLAST can be utilized as described in Altschul et al., Nucleic Acids Res 25(17): 3389-3402 (1997). When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. In some embodiments, a polypeptide or polynucleotide has 70%, at least 70%, 75%, at least 75%, 80%, at least 80%, 85%, at least 85%, 90%, at least 90%, 95%, at least 95%, 97%, at least 97%, 98%, at least 98%, 99%, or at least 99% or 100% sequence identity with a reference polypeptide or polynucleotide (or a fragment of the reference polypeptide or polynucleotide) provided herein. In some embodiments, a polypeptide or polynucleotide have about 70%, at least about 70%, about 75%, at least about 75%, about 80%, at least about 80%, about 85%, at least about 85%, about 90%, at least about 90%, about 95%, at least about 95%, about 97%, at least about 97%, about 98%, at least about 98%, about 99%, at least about 99% or about 100% sequence identity with a reference polypeptide or polynucleotide (or a fragment of the reference polypeptide or nucleic acid molecule) provided herein. As used herein, a “complex” refers to a group of two or more associated polynucleotides and / or polypeptides. In the context of complex formation, the terms “associate” or “association” refers to molecules bound to one another through electrostatic, hydrophobic / hydrophilic, and / or hydrogen bonding interaction, without being covalently attached. A molecule that comprises different moieties covalently attached to one another is known. In some embodiments, a complex is formed when all the components of the complex are present together, i.e., a self-assembling complex. In some embodiments, a complex is formed through chemical interactions between different components of the complex such as, for example, hydrogen-bonding. In some embodiments, the polynucleotides provided herein form a complex with the proteins provided herein through secondary structure recognition of the polynucleotide by the protein. In some embodiments, the Cas-binding region of the polynucleotides provided herein comprise a secondary structure recognized by a Cas nuclease, Cas nickase, or Cas fusion protein provided herein. The terms “insertion precision” or “precision of insertion” or “precise editing” are used to describe the degree of accuracy of insertion of an insert nucleotide sequence into a target sequence. In other words, a high insertion precision is an insertion of the nucleotide sequence into the target sequence without mutations and / or additional insertions and / or deletions in the genome. Insertion precision can be quantified by Next-Gen sequencing. Insertion precision will be the ratio % of reads that perfectly aligns with the intended genomic insertion to the total % of reads with insertion or deletions. A value of 1.0 will mean absolute precision, whereas a value of 0.0 will mean complete absence of precision. For example, an insertion of an inserted nucleotide sequence into a target sequence can have a precision of 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1 or 0.0. For measuring longer sequence integration, the following equation can be used where the average insertion length at the cut site can be calculated by dividing the sum of the weighted frequency of reads for each insertion size by the sum of the total amount of inserted reads. This quantifiable measure of insertion length can be used to describe the Artemis knockout / modulation phenotype. The terms “editing efficiency” or “efficiency of inserting a nucleotide sequence” or “efficiency of inserting a sequence of interest” refers to rate with which nucleotides are inserted into the target sequences. Therefor increases in editing or inserting of nucleotide sequences may refer to a higher frequency of integration of nucleotide sequences into a target sequence compared to a control editing or inserting event. It may also refer to an increase in the length of the nucleotide sequences which are inserted at an editing or inserting event compared to a control editing or inserting event. For example, an increase in the efficiency of a “editing efficiency” or “efficiency of inserting a nucleotide sequence” or “efficiency of inserting a sequence of interest” can be at least 1%, 5%, 10,%, 20%, 50%, 100%, 500% or more. Any changes in editing efficiency of an editing or inserting event compared to a control editing or inserting event can be measured by the method described in the present disclosure. Cas Proteins Cas Fusion Proteins In some embodiments, the disclosure provides a Cas fusion protein comprising: (i) a Cas nuclease and (ii) a reverse transcriptase, or a DNA polymerase, or a DNA ligase, wherein the Cas nuclease is capable of generating a double-stranded polynucleotide cleavage. As described herein, Cas fusion proteins typically include at least two domains having different functions. In some embodiments, the Cas fusion protein comprises a Cas nuclease. In general, Cas nucleases are part of a CRISPR / Cas system. As described herein, CRISPR / Cas systems can be utilized for site-specific genome modifications. A CRISPR / Cas system can include a Cas nuclease and a guide polynucleotide (e.g., a guide RNA). In some embodiments, the guide polynucleotide comprises a polypeptide-binding segment, which binds and / or activates the Cas nuclease, and a guide sequence (e.g., crRNA), which hybridizes to a target sequence. As used herein, a “segment” refers to a part, section, or region of a molecule, e.g., a contiguous stretch of nucleotides of a guide polynucleotide molecule. The definition of “segment,” unless otherwise specifically defined, is not limited to a specific number of total base pairs. In some embodiments, the guide polynucleotide comprises a tracrRNA. In some embodiments, the guide polynucleotide does not comprise a tracrRNA, and the tracrRNA is provided as a separate polynucleotide in the CRISPR / Cas system. In some embodiments, the tracrRNA activates the Cas nuclease. In some embodiments, activation of the Cas nuclease initiates or increases its nuclease activity. In some embodiments, activation of the Cas nuclease comprises binding of the nuclease to a target sequence in a target polynucleotide. CRISPR / Cas systems can be classified as Types I to VI, based on the nuclease protein in the system. For example, Cas9 can be found in Type II systems, while Cas12 can be found in Type V systems. Each Type can be further divided into subtypes. For example, Type II can include subtypes II-A, II-B, and II-C, and Type V can include subtypes V-A and V-B. Classification of CRISPR / Cas systems and Cas nucleases is further discussed in, e.g., Makarova et al., Methods Mol Biol 1311:47-75 (2015); Makarova et al., The CRISPR Journal Oct 2018; 325-336; and Koonin et al., Phil Trans R Soc B 374:20180087 (2018). Cas nucleases described herein can encompass any Type or variant, unless otherwise specified. In some embodiments, the Cas nuclease is capable of generating a double-stranded polynucleotide cleavage, e.g., a double-stranded DNA cleavage. In general, a Cas nuclease can include one or more nuclease domains, such as RuvC and HNH, and can cleave double- stranded DNA. In some embodiments, a Cas nuclease comprises a RuvC domain and an HNH domain, each of which cleaves one strand of double-stranded DNA. In some embodiments, the Cas nuclease generates blunt ends. In some embodiments, the RuvC and HNH of a Cas nuclease cleaves each DNA strand at the same position, thereby generating blunt ends. In some embodiments, the Cas nuclease generates cohesive ends. In some embodiments, the RuvC and HNH of a Cas nuclease cleaves each DNA strand at different positions (i.e., cut at an “offset”), thereby generating cohesive ends. As used herein, the terms “cohesive ends,” “staggered ends,” or “sticky ends” refer to a nucleic acid fragment with strands of unequal length. In contrast to “blunt ends,” cohesive ends are produced by a staggered cut on a double-stranded nucleic acid (e.g., DNA). A sticky or cohesive end has protruding singles strands with unpaired nucleotides, or “overhangs,” e.g., a 3’ or a 5’ overhang. In some embodiments, the Cas nuclease is Cas9. Cas9 is found in Type II CRISPR / Cas systems as described herein. Exemplary Cas9 proteins include, but are not limited to, the Cas9 protein from Streptococcus pyogenes, Streptococcus thermophilus, Streptococcus mutans, Listeria innocua, Neisseria meningitidis, Staphylococcus aureus, Klebisella pneumoniae, and numerous other bacteria. Further exemplary Cas9 nucleases are described in, e.g., US 8,771,945, US 9,023,649, US 10,000,772, and US 10,407,697. In some embodiments, the Cas9 is a Type IIB Cas9. In general, Type IIB Cas9 proteins are capable of generating cohesive ends, as described herein. Exemplary Type IIB Cas9 proteins include, but are not limited to, the Cas9 protein from Legionella pneumophila, Francisella novicida, Parasutterella excrementihominis, Sutterella wadsworthensis, Wolinella succinogenes, and numerous other bacteria. In some embodiments, the Type IIBCas9 is from the sequenced gut metagenome MH0245_GL0161830.1 (MHCas9). Further Type IIB Cas9 proteins are described in, e.g., WO 2019 / 099943. In some embodiments, the Cas nuclease is Cas12. Cas12 nucleases are sometimes known as “Cpf1” or “C2c1” nucleases and are found in Type V CRISPR / Cas systems as described herein. Cas12 nuclease are typically smaller than Cas9 nucleases and are capable of generating cohesive ends. Exemplary Cas12 proteins include, but are not limited to, the Cas12 protein from Francisella novicida, Acidaminococcus sp., Lachnospiraceae sp., Prevotella sp., and numerous other bacteria. Further Cas12 nuclease are described in, e.g., US 9,580,701, US 2016 / 0208243, Zetsche et al., Cell 163(3):759-771 (2015), and Chen et al., Science 360:436-439 (2018). In some embodiments, the Cas nuclease is Cas14. Cas14 nucleases, originally discovered in archaea, are small enzymes that typically target single-stranded DNA (ssDNA) and do not require a PAM sequence. Cas14 can be found in the DPANN superphylum of Archaea and are further described in, e.g., Harrington et al., Science 362:839-842 (2018) and US 2020 / 0087640. In some embodiments, the Cas fusion protein comprises a Cas nuclease and a reverse transcriptase, a DNA polymerase, a DNA ligase, or a combination thereof. In some embodiments, the Cas fusion protein comprises reverse transcriptase. Reverse transcriptase (sometimes abbreviated as RT) is an enzyme used to generate DNA (e.g., complementary DNA or cDNA) from an RNA template, a process called reverse transcription. A typical reverse transcription reaction is initiated with RNA template and a primer that binds to an end of the RNA template. In some embodiments, the reverse transcriptase binds to the primer (e.g., PBS) and synthesizes a strand of cDNA (e.g., based on the RNA template) in a process to provide a first cDNA. In some embodiments, an RNase, e.g., RNase H, removes the RNA template. In some embodiments, the reverse transcriptase comprises RNase activity, e.g., RNase H. In some embodiments, a DNA strand complementary to the first cDNA is then synthesized by DNA polymerase to generate a double-stranded sequence. In some embodiments, the reverse transcriptase comprises DNA polymerase activity. In some embodiments, DNA repair mechanisms, e.g., NHEJ, can be used to insert the double stranded sequence comprising the sequence of interest into the double stranded polynucleotide. Exemplary reverse transcriptases include, but are not limited to, AMV reverse transcriptase, MMLV (M-MuLV) reverse transcriptase, R2 reverse transcriptase, and HIV reverse transcriptase. In some embodiments, the reverse transcriptase is MMLV reverse transcriptase or R2 reverse transcriptase. In some embodiments, the reverse transcriptase is capable of DNA polymerase activity. In some embodiments, the Cas nuclease of the Cas fusion protein generates a double- stranded polynucleotide cleavage at a target sequence in a target polynucleotide, e.g., a target DNA sequence. In some embodiments, one strand of the cleaved DNA serves as a primer for the reverse transcriptase of the fusion protein. In some embodiments, a template polynucleotide containing a template sequence for the reverse transcriptase is provided, and the reverse transcriptase generates a first cDNA. In some embodiments, the template sequence is RNA, and an RNase removes the template sequence. In some embodiments, the reverse transcriptase comprises RNase activity. In some embodiments, the template sequence is removed by a separate RNase. In some embodiments, the RNase is RNase H. In some embodiments, a DNA strand complementary to the first cDNA is generated by a DNA polymerase, e.g., a separate DNA polymerase or a reverse transcriptase having DNA polymerase activity. In some embodiments, the first cDNA and the DNA strand complementary to the first cDNA hybridize to form a double-stranded sequence. In some embodiments, the double-stranded sequence is capable of being inserted into the cleaved target sequence. In some embodiments, the double-stranded sequence is inserted into the cleaved target sequence by a DNA repair pathway. In some embodiments, the DNA repair pathway is non-homologous end joining (NHEJ), microhomology mediated end joining (MMEJ), homology directed repair (HDR), or a combination thereof. In some embodiments, the double-stranded sequence is inserted into the cleaved target sequence by ligation, e.g., using a DNA ligase. In some embodiments, the Cas fusion protein comprises DNA polymerase. DNA polymerase is an enzyme that synthesizes DNA by adding nucleotides to an existing single DNA strand. In some embodiments, DNA polymerase generates a double-stranded sequence from a first synthesized strand generated by reverse transcriptase. In some embodiments, DNA polymerase generates double-stranded DNA from a single-stranded DNA template (ssDNA). In some embodiments, the Cas nuclease of the Cas fusion protein generates a double- stranded polynucleotide cleavage at a target sequence in a target polynucleotide, e.g., a target DNA sequence. In some embodiments, a template polynucleotide, e.g., an ssDNA template, is provided, and the DNA polymerase of the Cas fusion protein generates a double-stranded sequence from the ssDNA template. In some embodiments, the double- stranded sequence is capable of being inserted into the cleaved target sequence. In some embodiments, the double-stranded sequence is inserted into the cleaved target sequence by a DNA repair pathway. In some embodiments, the DNA repair pathway is non-homologous end joining (NHEJ), microhomology mediated end joining (MMEJ), or homology directed repair (HDR). In some embodiments, the double-stranded sequence is inserted into the cleaved target sequence by ligation, e.g., using a DNA ligase. Exemplary DNA polymerases include, but are not limited to, DNA Polymerase (Pol) I, II, III, IV, and V; DNA polymerase (Pol) α, β, λ, γ, σ, μ, δ, ε, η, ι, κ, ζ, θ, Rev1, and Rev3; isothermal DNA polymerases including, e.g., Bst, T4, and Φ29 (phi29) DNA polymerase; and thermostable DNA polymerases including, e.g., Taq, Pfu, KOD, Tth, and Pwo DNA polymerase. In some embodiments, the DNA polymerase is part of a DNA repair pathway. In some embodiments, the DNA repair pathway DNA polymerase is Pol β, Pol γ, Pol σ, or Pol μ. In some embodiments, the DNA polymerase is Rev3. DNA repair pathways are further described herein. In some embodiments, the DNA polymerase has high processivity, i.e., the DNA polymerase can process a large number of nucleotides in a single binding event. In some embodiments, the high processivity DNA polymerase is capable of greater than 100 bp, greater than 200 bp, greater than 300 bp, greater than 400 bp, greater than 500 bp, greater than 600 bp, greater than 700 bp, greater than 800 bp, greater than 1 kb, greater than 5 kb, greater than 10 kb, greater than 50 kb, or greater than 100 kb per binding event. In some embodiments, a high processivity DNA polymerase is advantageous for synthesizing long templates and sequences with secondary structures such as high GC content. In some embodiments, the high processivity DNA polymerase is Pol α, Pol δ, Pol ε, or Φ29 DNA polymerase. In some embodiments, the DNA polymerase is phi29 DNA polymerase, T4 DNA polymerase, DNA polymerase μ (mu), DNA polymerase δ (delta), or DNA polymerase ε (epsilon). In some embodiments, the DNA polymerase of the Cas fusion protein comprises a catalytically active fragment or truncation of a DNA polymerase. As used herein, a “catalytically active” fragment, truncation, or domain of an enzyme means that the fragment or truncation has substantially the same activity as the full-length or wild- type form of the enzyme (e.g., DNA polymerase). In some embodiments, a catalytically active fragment, truncation, or domain of an enzyme herein has about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190%, about 200%, or greater than 200% of the activity of full-length or wild-type enzyme (e.g., DNA polymerase). In some embodiments, a catalytically active truncation, fragment, or domain of an enzyme herein has one or more improved properties as compared to the full-length or wild-type enzyme (e.g., DNA polymerase), such as improved stability and / or processivity. In some embodiments, the DNA polymerase is a Klenow fragment of E. coli DNA Polymerase I. In some embodiments, the DNA polymerase is a truncation of Rev3 as described in Lee et al., PNAS (2014), doi: 10.1073 / pnas.1324001111. In some embodiments, the Cas fusion protein comprises a DNA ligase. DNA ligase is an enzyme that facilitates the joining of DNA strands together by catalyzing the formation of a phosphodiester bond. DNA ligases can repair single- or double-stranded breaks in DNA. In some embodiments, DNA ligase ligates single-stranded DNA. In some embodiments, DNA ligase ligates blunt ends of double-stranded DNA. In some embodiments, DNA ligase ligates cohesive ends of double-stranded DNA. In some embodiments, the DNA ligase facilitates the recombination of a double-stranded insertion sequence into a double stranded polynucleotide. In some embodiments, when two double-stranded polynucleotide cleavages occur in the target polynucleotide (e.g., at a first target site and a second target site), the DNA ligase can facilitate the recombination of the double-stranded polynucleotide, thereby eliminating the sequence between the first target site and the second target site. In some embodiments, the Cas nuclease of the Cas fusion protein generates a double- stranded polynucleotide cleavage at a target sequence in a target polynucleotide, e.g., a target DNA sequence. In some embodiments, a template polynucleotide, e.g., a DNA template, is provided, and the DNA ligase of the Cas fusion protein ligates the template polynucleotide to the cleaved target sequence. In some embodiments, the DNA template is a double stranded polynucleotide comprising blunt ends. In some embodiments, the DNA template is a double stranded polynucleotide comprising cohesive ends. In some embodiments, the DNA template is a single stranded polynucleotide. Exemplary DNA ligases include, but are not limited to, E. coli DNA ligase, Taq DNA ligase, T4 DNA ligase, T7 DNA ligase, DNA ligase I, III, and IV, and Ampligase DNA ligase. In some embodiments, the DNA ligase is T4 ligase. In some embodiments, the Cas fusion protein further comprises a DNA-binding or an RNA- binding domain. In some embodiments, the DNA-binding or RNA-binding domain of the Cas fusion protein brings the Cas fusion protein and the template polynucleotide in proximity to one another. In some embodiments, the DNA-binding or RNA-binding domain promotes binding of the template polynucleotide to the fusion protein. In some embodiments, the DNA-binding or RNA-binding domain improves efficiency of the reverse transcriptase, the DNA polymerase, or the DNA ligase reaction by bringing the template polynucleotide and the Cas fusion protein in proximity to one another. In some embodiments, the DNA-binding or RNA-binding domain increases efficiency of incorporating the double-stranded sequence resulting from the reverse transcriptase or DNA polymerase reaction into the cleaved target sequence. In some embodiments, the Cas fusion protein further comprises a DNA-binding domain. Thus, in some embodiments, the Cas fusion protein comprises a Cas nuclease, a reverse transcriptase, and an DNA-binding domain. In some embodiments, the Cas fusion protein comprises a Cas nuclease, a DNA polymerase, and an DNA-binding domain. In some embodiments, the Cas fusion protein comprises a Cas nuclease, a DNA ligase, and an DNA- binding domain. DNA-binding domains can be found as part of viral, bacterial, and eukaryotic (e.g., mammalian) transcription factors. In some embodiments, the DNA- binding domain binds to single-stranded DNA. In some embodiments, the DNA-binding domain binds to double-stranded DNA. In some embodiments, the DNA-binding protein binds to both single-stranded and double-stranded DNA. Exemplary DNA-binding domains that bind double-stranded DNA include, but are not limited to, helix-turn-helix (HTH), zinc finger (ZF), transcription activation like effector (TALE), small nuclear RNA activating protein (SNAP), leucine zipper, winged helix, helix-loop-helix, HMG-box, Wor3, and OB-fold. Exemplary DNA-binding domains that bind to single-stranded DNA include, but are not limited to, T4 Gene 32 Protein (T4g32), HUH enzymes such as the viral Rep protein, and Far upstream element-binding protein 1 (FUBP). Further DNA- binding domains are provided, e.g., in Alberts B et al. Molecular Biology of the Cell.4th edition. New York: Garland Science; 2002. DNA-Binding Motifs in Gene Regulatory Proteins; Yesudhas et al., Genes (Basel) 8(8): 192 (2017); and Vidangos et al., Biopolymers 99(12): 1082-1096 (2013). In some embodiments, the DNA-binding domain is a zinc finger DNA-binding domain, a transcription factor, or an adeno-associated virus Rep protein. In some embodiments, the DNA-binding domain is Far upstream element-binding protein (FUBP). In some embodiments, the Cas fusion protein further comprises an RNA-binding domain. Thus, in some embodiments, the Cas fusion protein comprises a Cas nuclease, a reverse transcriptase, and an RNA-binding domain. In some embodiments, the Cas fusion protein comprises a Cas nuclease, a DNA polymerase, and an RNA-binding domain. In some embodiments, the Cas fusion protein comprises a Cas nuclease, a DNA ligase, and an RNA- binding domain. RNA-binding domains can be found as part of RNA processing proteins, e.g., involved in RNA biogenesis, maturation, transport, cellular localization, and stability. In some embodiments, the RNA-binding domain comprises a RNA-recognition motif. In some embodiments, the RNA-binding domain comprises a double-stranded RNA-binding motif. In some embodiments, the RNA-binding domain comprises a zinc finger. In some embodiments, the RNA-binding domain comprises a KH domain such as, e.g., heterogeneous nuclear ribonucleoprotein K (hnRNPK). Exemplary RNA-binding domains include, but are not limited to, NOVA1, ADAR, CPSF, TAP / NXF1:p15, ZBP1, Elav, Sxl, tra-2, FOG-1, MOG-1, MOG-4, MOG-5, RNP-4, GLD-1, GLD-3, DAZ-1, PGL1, OMA- 1, OMA2, MEC-8, UNC-75, EXC-7, Pumilio, Nanos, FMRP, CPEB, Staufen 1, FXR1, and MCP2. Further RNA-binding domains are provided, e.g., in Lunde et al., Nat Rev Mol Cell Biol 8(6): 479-490 (2007) and Glisovic et al., FEBS Lett 582(14): 1977-1986 (2008). In some embodiments, the RNA-binding domain is MS2 coat protein (MCP2). In some embodiments, the RNA-binding domain comprises a KH domain. In some embodiments, the RNA-binding domain is hnRNPK. In some embodiments, the Cas fusion protein further comprises a nuclear localization signal (NLS). As used herein, "nuclear localization signal" or "nuclear localization sequence" (NLS) refers to a polypeptide that "tags" a protein for import into the cell nucleus by nuclear transport, i.e., a protein having a NLS is transported into the cell nucleus. Typically, the NLS includes positively-charged Lys or Arg residues exposed on the protein surface. Exemplary nuclear localization sequences include, but are not limited to, the NLS from: SV40 Large T-Antigen, nucleoplasmin, EGL-13, c-Myc, and TUS-protein. Nucleotides Sequence of Interest In some embodiments, a polynucleotide of interest of the disclosure is an exogenous polynucleotide which comprises a sequence of interest (SOI) to be inserted into the genome of a eukaryotic cell. In some embodiments, the sequence of interest encodes a gene of interest. In some embodiments, the polynucleotide comprising exogenous polynucleotide comprising a SOI is an exogenous polynucleotide template which is inserted into the genome of a eukaryotic cell via CRISPR / Cas-mediated homologous recombination. In some embodiments, the SOI comprises at least one mutation of interest to be inserted into a genome of a eukaryotic cell. In some embodiments, the SOI comprises a gene of interest to be inserted into a genome of a eukaryotic cell. In some embodiments, the SOI can be introduced as an exogenous polynucleotide template. In some embodiments, the SOI is a hybrid polynucleotide comprising single-stranded and double-stranded regions. In some embodiments, the hybrid polynucleotide comprises double-stranded sequences at the 5’ and 3’ ends and an internal single-stranded sequence (Shy et al, bioRxiv, 2021, preprint published 9 / 2 / 2021). In some embodiments, the exogenous polynucleotide includes blunt ends. In some embodiments, the exogenous polynucleotide template includes cohesive ends. In some embodiments, the exogenous polynucleotide template includes cohesive ends complementary to cohesive ends in the target sequence. The exogenous polynucleotide template can be of any suitable length, such as about or at least about 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 500, 1000, 5000, or 10,000 or more nucleotides in length. In some embodiments, the exogenous polynucleotide template is complementary to a portion of a polynucleotide including the target sequence. In some embodiments, when optimally aligned, the exogenous polynucleotide template overlaps with one or more nucleotides of a target sequence (e.g., about or at least about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, or 100 or more nucleotides). In some embodiments, when the exogenous polynucleotide template and a polynucleotide including the target sequence are optimally aligned, the nearest nucleotide of the exogenous polynucleotide template is within about 1, 5, 10, 15, 20, 25, 50, 75, 100, 200, 300, 400, 500, 100, 1500, 2000, 2500, 5000, 10,000 or more nucleotides from the target sequence. In some embodiments, the exogenous polynucleotide is DNA, such as, e.g., a DNA plasmid, a bacterial artificial chromosome (BAC), a yeast artificial chromosome (YAC), a viral vector, a linear piece of single-stranded or double-stranded DNA, an oligonucleotide, a PCR fragment, a naked nucleic acid, or a nucleic acid complexed with a delivery vehicle such as a liposome. In some embodiments, the exogenous polynucleotide is RNA. In some embodiments, the RNA is a messenger RNA (mRNA). In some embodiments, the exogenous polynucleotide is inserted into the target sequence using an endogenous DNA repair pathway of the cell. In some embodiments, the endogenous DNA repair pathway is HDR. During the repair process, an exogenous polynucleotide template including the SOI can be introduced into the target sequence. In some embodiments, an exogenous polynucleotide template including the SOI flanked by an upstream sequence and a downstream sequence is introduced into the cell, where the upstream and downstream sequences share sequence similarity with either side of the site of integration in the target sequence. In some embodiments, the exogenous polynucleotide including the SOI includes, for example, a mutated gene. In some embodiments, the exogenous polynucleotide includes a sequence endogenous or exogenous to the cell. In some embodiments, the SOI includes polynucleotides encoding a protein, or a non-coding sequence such as, e.g., a microRNA. In some embodiments, the SOI is operably linked to a regulatory element. In some embodiments, the SOI is a regulatory element. In some embodiments, the SOI includes a resistance cassette, e.g., a gene that confers resistance to an antibiotic. In some embodiments, the SOI includes a mutation of the wild-type target sequence. In some embodiments, the SOI disrupts or corrects the target sequence by creating a frameshift mutation or nucleotide substitution. In some embodiments, the SOI includes a marker. Introduction of a marker into a target sequence can make it easy to screen for targeted integrations. In some embodiments, the marker is a restriction site, a fluorescent protein, or a selectable marker. In some embodiments, the SOI is introduced as a vector including the SOI. The upstream and downstream sequences in the exogenous polynucleotide template are selected to promote homologous recombination between the target sequence and the exogenous polynucleotide. The upstream sequence is a nucleic acid sequence that shares sequence similarity with the sequence upstream of the targeted site for integration (i.e., the target sequence). Similarly, the downstream sequence is a nucleic acid sequence that shares sequence similarity with the sequence downstream of the targeted site for integration. Thus, in some embodiments, the exogenous polynucleotide template including the SOI is inserted into the target sequence by homologous recombination at the upstream and downstream sequences. In some embodiments, the upstream and downstream sequences in the exogenous polynucleotide template have at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% sequence identity with the upstream and downstream sequences of the targeted genome sequence, respectively. In some embodiments, the upstream or downstream sequence has at least about 20, 50, 100, 150, 200, 250, 300, 350, 400, or 500 base pairs and up to about 600, 750, 1000, 1250, 1500, 1750 or 2000 base pairs. In some embodiments, the upstream or downstream sequence has about 20 to 2000 base pairs, or about 50 to 1750 base pairs, or about 100 to 1500 base pairs, or about 200 to 1250 base pairs, or about 300 to 1000 base pairs, or about 400 to about 750 base pairs, or about 500 to 600 base pairs. In some embodiments, the upstream or downstream sequence has about 50, about 100, about 250, about 500, about 100, about 1250, about 1500, about 1750, about 2000, about 2250, or about 2500 base pairs. In some embodiments, the SOI comprises a gene of interest. As used herein, the term “gene of interest” refers to a gene that encodes a biomolecule of interest (e.g., a protein or an RNA molecule). In some embodiments, the gene of interest encodes a protein of interest. In some embodiments, the protein of interest comprises an intracellular protein, a membrane protein, an extracellular protein, or combination thereof. In some embodiments, the protein of interest comprises a nuclear protein, a transcription factor, a nuclear membrane transporter, an intracellular organelle associated protein, a membrane receptor, a catalytic protein, an enzyme, a therapeutic protein, a membrane protein, a membrane transport protein, a signal transduction protein, an immunological protein, or combination thereof. In some embodiments, the immunological protein comprises an antibody, e.g., IgG, IgA, IgM, IgD, IgE, or combination thereof. In some embodiments, the immunological protein is a T cell receptor (TCR). In some embodiments, immunological protein is a chimeric antigen receptor (CAR). In some embodiments, the SOI encodes a copy of a native gene of the host cell. In some embodiments, the SOI encodes a copy of a native gene that is deficient in the host cell. In some embodiments, the host cell comprises a mutation in a gene, and the SOI encodes a wild-type copy of the gene. In some embodiments, the host cell comprises a wild-type gene, and the SOI encodes a copy of the gene comprising a mutation of interest. In some embodiments, the SOI encodes a heterologous gene that is not naturally occurring in the host cell. In some embodiments, the gene of interest encodes an RNA of interest. In some embodiments, the RNA of interest comprises a therapeutic RNA. In some embodiments, the RNA of interest comprises messenger RNA (mRNA), transfer RNA (tRNA), ribosomal RNA (rRNA), small nuclear RNA (snRNA), antisense RNA, microRNA (miRNA), small interfering RNA (siRNA), cell-free RNA (cfRNA), or combination thereof. In some embodiments, the sequence of interest comprises a regulatory element of interest. In some embodiments, the SOI is inserted into a target polynucleotide of a host cell, such that the regulatory element on the sequence of interest is capable of regulating a native gene of the host cell. Regulatory elements are described herein and include, e.g., promoters, enhancers, silencers, operators, response elements, 5’ UTR, 3’ UTR, insulators, and the like. In some embodiments, the polynucleotide comprising a SOI is about 1 nucleotide to about 5000 nucleotides in length. In some embodiments, the polynucleotide comprising the SOI is about 5 nucleotides to about 5000 nucleotides in length. In some embodiments, polynucleotide comprising a SOI is about 6 nucleotides to about 1000 nucleotides in length. In some embodiments, the polynucleotide comprising a SOI is about 7 nucleotides to about 750 nucleotides in length. In some embodiments, the polynucleotide comprising a SOI is about 8 nucleotides to about 500 nucleotides in length. In some embodiments, the polynucleotide comprising a SOI is about 9 nucleotides to about 250 nucleotides in length. In some embodiments, the polynucleotide comprising a SOI is about 10 nucleotides to about 100 nucleotides in length. In some embodiments, the polynucleotide comprising a SOI is about 15 nucleotides to about 90 nucleotides in length. In some embodiments, the polynucleotide comprising a SOI is about 20 nucleotides to about 80 nucleotides in length. In some embodiments, the polynucleotide comprising a SOI is about 25 nucleotides to about 70 nucleotides in length. In some embodiments, the polynucleotide comprising a SOI is about 30 nucleotides to about 50 nucleotides in length. In some embodiments, the polynucleotide comprising a SOI is about 1 to about 10 nucleotides in length. In some embodiments, the polynucleotide comprising a SOI is about 1 to about 20 nucleotides in length. In some embodiments, the polynucleotide comprising a SOI is about 1 to about 30 nucleotides in length. In some embodiments, the polynucleotide comprising a SOI is about 10 to about 40 nucleotides in length. In some embodiments, the polynucleotide comprising a SOI is about 1 to about 50 nucleotides in length. In some embodiments, the polynucleotide comprising a SOI is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 nucleotides in length. In some embodiments, the polynucleotide comprising a SOI is greater than about 10 nucleotides, greater than about 15 nucleotides, greater than about 20 nucleotides, greater than about 25 nucleotides, greater than about 30 nucleotides, greater than about 35 nucleotides, greater than about 40 nucleotides, greater than about 45 nucleotides, or greater than about 50 nucleotides in length. In some embodiments, the SOI is about 3 to about 5000 nucleotides in length. In some embodiments, the SOI is about 4 to about 1000 nucleotides in length. In some embodiments, the SOI is about 5 to about 900 nucleotides in length. In some embodiments, the SOI is about 6 to about 800 nucleotides in length. In some embodiments, the SOI is about 7 to about 700 nucleotides in length. In some embodiments, the SOI is about 8 to about 600 nucleotides in length. In some embodiments, the SOI is about 9 to about 500 nucleotides in length. In some embodiments, the SOI is about 50 to about 5000 nucleotides in length. In some embodiments, the SOI is about 60 to about 1000 nucleotides in length. In some embodiments, the SOI is about 70 to about 900 nucleotides in length. In some embodiments, the SOI is about 8 to about 800 nucleotides in length. In some embodiments, the SOI is about 90 to about 700 nucleotides in length. In some embodiments, the SOI is about 100 to about 500 nucleotides in length. In some embodiments, the SOI is about 100 to about 250 nucleotides in length. In some embodiments, the SOI is about 10 to about 90 nucleotides in length. In some embodiments, the SOI is about 11 to about 80 nucleotides in length. In some embodiments, the SOI is about 12 to about 70 nucleotides in length. In some embodiments, the SOI is about 15 to about 60 nucleotides in length. In some embodiments, the SOI is about 10 to about 50 nucleotides in length. In some embodiments, the SOI is about 1 to about 10 nucleotides in length. In some embodiments, the SOI is about 1 to about 25 nucleotides in length. In some embodiments, the SOI is about 1 to about 50 nucleotides in length. In some embodiments, the SOI is about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 nucleotides in length. In some embodiments, the SOI is greater than about 10 nucleotides, greater than about 15 nucleotides, greater than about 20 nucleotides, greater than about 25 nucleotides, greater than about 30 nucleotides, greater than about 35 nucleotides, greater than about 40 nucleotides, greater than about 45 nucleotides, or greater than about 50 nucleotides in length. ii. Cas and Cas-associated polynucleotides In some embodiments, the present disclosure encompasses polynucleotide sequences which encode a Cas protein of the disclosure, i.e., a Cas polynucleotide. In some embodiments, a polynucleotide of the disclosure is capable of forming a complex with a Cas protein. In some embodiments, the polynucleotide capable of forming a complex with a Cas protein comprise a guide sequence. In some embodiments, the polynucleotide capable of forming a complex with a Cas protein comprises a Cas-binding region. In some embodiments, the polynucleotide capable of forming a complex with a Cas protein comprises a DNA template sequence. In some embodiments, the polynucleotide capable of forming a complex with a Cas protein comprises a guide sequence, a Cas-binding region, and a DNA template sequence, or any combination thereof. In some embodiments, the polynucleotide comprises, in 5’ to 3’ order, a guide sequence, a Cas-binding region, and a DNA template sequence. In some embodiments, the guide sequence is capable of hybridizing with a target polynucleotide, e.g., a target polynucleotide in a genome of a host cell also referred to as target genomic locus. In embodiments, the guide sequence is complementary to the target polynucleotide. In some embodiments, the target polynucleotide is a target DNA intended to be cleaved by the Cas nuclease . In some embodiments, the guide sequence comprises RNA, i.e., an RNA guide sequence. In some embodiments, the guide sequence comprises a combination of RNA and DNA. Hybrid RNA-DNA guide sequences are further described in, e.g., Rueda et al., Nat Comm 8:1610 (2017). In some embodiments, the guide sequence is about 10 to about 40 nucleotides in length. In some embodiments, the guide sequence is about 12 to about 30 nucleotides in length. In some embodiments, the guide sequence is about 15 to about 20 nucleotides in length. In some embodiments, the guide sequence is about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, or about 40 nucleotides in length. In some embodiments, the guide sequence is a sufficient length for hybridizing to the target polynucleotide. In some embodiments, the Cas-binding region is capable of binding to the Cas protein (e.g., Cas nuclease ), thereby forming a complex with the Cas protein. In some embodiments, the Cas-binding region comprises RNA. In some embodiments, the Cas-binding region comprises a combination of RNA and DNA. Hybrid RNA-DNA sequences that can bind to and / or activate Cas proteins are further described in, e.g., Rueda et al., Nat Comm 8:1610 (2017). In some embodiments, multiple guide RNA as described in the methods, kits, and compositions described herein can be used during the same method, kit or composition. For example, in some embodiments, 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more different guide RNA can be used at the same time. In some embodiments, the Cas-binding region comprises a tracrRNA that binds to and activates the Cas protein. In some embodiments, the Cas-binding region is capable of hybridizing with a tracrRNA, and the composition further comprises a tracrRNA. In some embodiments, the tracrRNA is capable of binding the Cas nuclease . In some embodiments, the tracrRNA is capable of activating the Cas nuclease . In some embodiments, the activating comprises initiating or increasing the cleavage activity of the Cas nuclease . In some embodiments, the activating comprises promoting binding of the Cas nuclease to a target polynucleotide (e.g., as guided by the guide sequence). In some embodiments, the activating comprises a combination of promoting binding of the Cas nuclease to the target polynucleotide; and initiating or increasing cleavage activity of the Cas nuclease . TracrRNA sequences of Cas proteins (e.g., Cas9, Cas12a, or Type II-B Cas proteins described herein) are available from public databases, including RNAcentral and Rfam, and further described in, e.g., Chylinski et al., RNA Biol 10(5):726-737 (2013) and Gasiunas et al., Nat Comm 11:5512 (2020). In some embodiments, the polynucleotide capable of forming a complex with a Cas molecule comprises a DNA template sequence at a 3’ end of the polynucleotide. In some embodiments, the DNA template sequence comprises single-stranded DNA. In some embodiments, the DNA template sequence comprises a sequence of interest. In some embodiments, the DNA template sequence comprises a primer binding sequence and a sequence of interest. In some embodiments, the DNA template sequence comprises a template for amplification by a DNA polymerase. In some embodiments, the sequence of interest comprises a template for amplification by a DNA polymerase. In some embodiments, the Cas nuclease of the composition is guided to a target polynucleotide by the guide sequence and cleaves the target polynucleotide, and one strand of the cleaved target polynucleotide hybridizes to the primer binding sequence and serves as a primer for a DNA polymerase. In some embodiments, the DNA polymerase is capable of synthesizing a DNA strand complementary to the SOI to form a double-stranded sequence comprising the SOI. In some embodiments, the double-stranded sequence comprising the SOI is inserted into the cleaved target polynucleotide, e.g., via ligation or a DNA repair pathway described herein. In some embodiments, the DNA template sequence is about 5 nucleotides to about 5000 nucleotides in length. In some embodiments, the DNA template sequence is about 6 nucleotides to about 1000 nucleotides in length. In some embodiments, the DNA template sequence is about 7 nucleotides to about 750 nucleotides in length. In some embodiments, the DNA template sequence is about 8 nucleotides to about 500 nucleotides in length. In some embodiments, the DNA template sequence is about 9 nucleotides to about 250 nucleotides in length. In some embodiments, the DNA template sequence is about 10 nucleotides to about 100 nucleotides in length. In some embodiments, the DNA template sequence is about 15 nucleotides to about 90 nucleotides in length. In some embodiments, the DNA template sequence is about 20 nucleotides to about 80 nucleotides in length. In some embodiments, the DNA template sequence is about 25 nucleotides to about 70 nucleotides in length. In some embodiments, the DNA template sequence is about 30 nucleotides to about 50 nucleotides in length. In some embodiments, the DNA template sequence is about 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 nucleotides in length. In some embodiments, the DNA template sequence is greater than about 10 nucleotides, greater than about 15 nucleotides, greater than about 20 nucleotides, greater than about 25 nucleotides, greater than about 30 nucleotides, greater than about 35 nucleotides, greater than about 40 nucleotides, greater than about 45 nucleotides, or greater than about 50 nucleotides in length. In some embodiments, the DNA template sequence comprises a primer-binding sequence. In some embodiments, the primer-binding sequence is about 3 to about 50 nucleotides in length. In some embodiments, the primer-binding sequence is about 4 to about 45 nucleotides in length. In some embodiments, the primer-binding sequence is about 5 to about 40 nucleotides in length. In some embodiments, the primer-binding sequence is about 6 to about 35 nucleotides in length. In some embodiments, the primer-binding sequence is about 7 to about 30 nucleotides in length. In some embodiments, the primer-binding sequence is about 8 to about 25 nucleotides in length. In some embodiments, the primer- binding sequence is about 10 to about 20 nucleotides in length. In some embodiments, the primer-binding sequence is about 4 to about 30 nucleotides in length. In some embodiments, the primer-binding sequence is about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 nucleotides in length. In some embodiments, the primer-binding sequence is of sufficient length to hybridize with a region of the cleaved target DNA sequence. In some embodiments, the polynucleotide comprising the DNA template sequence comprises a modified nucleotide, a non-B DNA structure, a DNA polymerase recruitment moiety, a DNA ligase recruitment moiety, or a combination thereof. In some embodiments, the polynucleotide comprising DNA template sequence comprises a modified nucleotide. In some embodiments, the modified nucleotide comprises an abasic site, a covalent linker, a xeno nucleic acid (XNA), a locked nucleic acid (LNA), a peptide nucleic acid (PNA), a phosphorothioate bond, a DNA lesion, a DNA photoproduct, a modified deoxyribonucleoside, a methylated nucleotide, or a combination thereof. In some embodiments, the modified nucleotide reduces or prevents overextension of the sequence of interest by the DNA polymerase. In some embodiments, reducing or preventing overextension of the sequence of interest by the DNA polymerase increases the precision of inserting the double-stranded sequence comprising the sequence of interest. In some embodiments, the modified nucleotide comprises an abasic site, also known as an apurinic / apyrimidinic (AP site). In some embodiments, the modified nucleotide comprises a covalent linker. In some embodiments, the covalent linker comprises a triethylene glycol (TEG) linker. In some embodiments, the covalent linker comprises an amino linker. TEG linkers and amino linkers have been shown to block polymerase extension; see, e.g., Strobel et al., bioRxiv doi:10.1101 / 2019.12.26.888743 (23 January 2020). In some embodiments, the modified nucleotide reduces or prevents nuclease degradation of a polynucleotide of the disclosure. In some embodiments, the modified nucleotide comprises a xeno nucleic acid (XNA). An XNA is a synthetic nucleotide analogue that has a different sugar group than the deoxyribose of DNA or the ribose of RNA. Exemplary sugar groups for XNA include, but are not limited to, threose, cyclohexene, glycol, or a locked ribose. In some embodiments, the XNA comprises 1,5-anhydrohexitol nucleic acid (HNA), cyclohexene nucleic acid (CeNA), threose nucleic acid (TNA), glycol nucleic acid (GNA), locked nucleic acid (LNA), and peptide nucleic acid (PNA). In some embodiments, the modified nucleotide comprises a locked nucleic acid (LNA), also known as a bridged nucleic acid (BNA). An LNA is a modified RNA nucleotide in which the ribose moiety is modified with an extra bridge connecting the 2’ oxygen and 4’ carbon. In some embodiments, the modified nucleotide comprises a peptide nucleic acid (PNA). Unlike the deoxyribose or ribose backbones of DNA or RNA, the backbone of a PNA polymer comprises N-(2-aminoethyl)-glycine units linked by peptide bonds, and the purine and pyrimidine bases are linked to the PNA backbone by a methylene bridge and a carbonyl group. In some embodiments, the modified nucleotide comprises a phosphorothioate bond. A phosphorothioate bond comprises a sulfur atom in place of one of the oxygens in the phosphate group linking two nucleotides. In some embodiments, the presence of an XNA, e.g., an LNA or a PNA, or a phosphorothioate bond in a polynucleotide increases stability of the polynucleotide against nuclease degradation. In some embodiments, the presence of a modified nucleotide in a polynucleotide (e.g., the polynucleotide of the composition provided herein) is capable of recruiting a DNA polymerase to the polynucleotide. In some embodiments, recruiting a DNA polymerase comprises: increasing the likelihood that a DNA polymerase recognizes the polynucleotide, e.g., due to presence of the modified nucleotide therein; promoting binding of a DNA polymerase to the polynucleotide; and / or activating a DNA polymerase, e.g., initiating or increasing activity of the DNA polymerase. In some embodiments, the recruited DNA polymerase binds to a strand of the cleaved target polynucleotide and extends the sequence of interest on the DNA template sequence, as described herein. In some embodiments, the modified nucleotide comprises a DNA lesion. As used herein, a “DNA lesion” refers to a region of a DNA polynucleotide containing a base alteration, base deletion, and / or sugar alteration typically indicative of DNA damage. DNA lesions can be caused by hydrolysis, oxidation, alkylation, depurination, depyrimidination, and / or deamination of a nucleobase. In some embodiments, the DNA lesion is capable of recruiting a DNA polymerase. In some embodiments, the DNA lesion comprises 8- oxoguanine, thymine-glycol, N7-(2-hydroxethyl)guanine (7HEG), 7-(2-oxoethyl)guanine, or a combination thereof. In some embodiments, the DNA lesion comprises 8-oxoguanine, thymine-glycol, or a combination thereof. In some embodiments, the modified nucleotide comprises a DNA photoproduct. DNA photoproducts are ultraviolet (UV)-induced DNA lesions and are further described in, e.g., Yokoyama et al., Int J Mol Sci 15(11):20321-20338 (2014). In some embodiments, the DNA photoproduct is capable of recruiting a DNA polymerase. In some embodiments, the DNA photoproduct comprises a pyrimidine dimer, a cyclobutane pyrimidine dimer (CPD), a pyrimidine (6-4) pyrimidone photoproduct (also referred to as a “(6-4) photoproduct”), an adenine-thymine heterodimer, a Dewar pyrimidinone, or a combination thereof. In some embodiments, the DNA photoproduct comprises CPD, a (6-4) photoproduct, or a combination thereof. In some embodiments, the modified nucleotide comprises a modified deoxyribonucleoside. In some embodiments, the modified deoxyribonucleoside is capable of recruiting a DNA polymerase. In some embodiments, the modified deoxyribonucleoside comprises a base not typically present in DNA, i.e., adenine, cytosine, guanine, or thymine. In some embodiments, the modified deoxyribonucleoside comprises deoxyuridine, acrolein- deoxyguanine, malondialdehyde-deoxyguanine, deoxyinosine, deoxyxanthosine, or a combination thereof. In some embodiments, the modified deoxyribonucleoside comprises deoxyuridine. In some embodiments, the modified nucleotide comprises one or more methylated nucleotides. In some embodiments, methylated nucleotides, e.g., methylated cytosines, are capable of recruiting a DNA polymerase. In some embodiments, the methylated nucleotide comprises 5-hydroxymethylcytosine, 5-methylcytosine, or a combination thereof. In some embodiments, the DNA template sequence comprises a non-B DNA structure. As used herein, “a non-B DNA structure” is a DNA secondary structural conformation that is not the canonical right-handed B-DNA helix. Non-limiting examples of non-B DNA structures include G-quadruplex, triplex DNA (H-DNA), Z-DNA, cruciform, slipped DNA strands, A-tract bending, sticky DNA. Non-B DNA structures are further described in, e.g., Guiblet et al., Nucleic Acids Res 49(3):1497-1516 (2021). In some embodiments, the non- B DNA structure is capable of recruiting a DNA polymerase. In some embodiments, the non-B DNA structure comprises a hairpin, a cruciform, Z-DNA, H-DNA (triplex DNA), G-quadruplex DNA (tetraplex DNA), slipped DNA, sticky DNA, or a combination thereof. In some embodiments, the DNA template sequence comprises a DNA polymerase recruitment moiety. DNA polymerase recruitment is described herein. Non-limiting examples of DNA polymerases that can be recruited by the DNA polymerase recruitment moiety include bacterial DNA polymerases such as Pol I (including a Klenow fragment thereof), Pol II, Pol III, Pol IV, or Pol V; eukaryotic DNA polymerases such as Pol α, Pol β, Pol λ, Pol γ, Pol σ, Pol μ, Pol δ, Pol ε, Pol η, Pol ι, Pol κ, Pol ζ, Pol θ, REV1, or REV3; isothermal DNA polymerases such as Bst, T4, or Φ29 (phi29) DNA polymerase; thermostable DNA polymerases such as Taq, Pfu, KOD, Tth, or Pwo DNA polymerase; or a variant or homologue thereof. In some embodiments, a polynucleotide of the disclosure can be chemically crosslinked to one or more moieties or conjugates which enhance the activity, cellular distribution, or cellular uptake of the polynucleotide. These moieties or conjugates can include conjugate groups covalently bound to functional groups such as primary or secondary hydroxyl groups. Conjugate groups include, but are not limited to, intercalators, reporter molecules, polyamines, polyamides, polyethylene glycols, polyethers, groups that enhance the pharmacodynamic properties of oligomers, and groups that enhance the pharmacokinetic properties of oligomers. Suitable conjugate groups include, but are not limited to, cholesterols, lipids, phospholipids, biotin, phenazine, folate, phenanthridine, anthraquinone, acridine, fluoresceins, rhodamines, coumarins, and dyes. Groups that enhance the pharmacodynamic properties include groups that improve uptake, enhance resistance to degradation, and / or strengthen sequence-specific hybridization with the target nucleic acid. Groups that enhance the pharmacokinetic properties include groups that improve uptake, distribution, metabolism or excretion of a subject nucleic acid. Conjugate moieties include but are not limited to lipid moieties such as a cholesterol moiety (Letsinger et al., Proc. Natl. Acad. Sci. USA, 1989, 86, 6553-6556), cholic acid (Manoharan et al., Bioorg. Med. Chem. Let., 1994, 4, 1053-1060), a thioether, e.g., hexyl-S-tritylthiol (Manoharan et al., Ann. N.Y. Acad. Sci., 1992, 660, 306-309; Manoharan et al., Bioorg. Med. Chem. Let., 1993, 3, 2765-2770), a thiocholesterol (Oberhauser et al., Nucl. Acids Res., 1992, 20, 533-538), an aliphatic chain, e.g., dodecandiol or undecyl residues (Saison- Behmoaras et al., EMBO J., 1991, 10, 1111-1118; Kabanov et al., FEBS Lett., 1990, 259, 327-330; Svinarchuk et al., Biochimie, 1993, 75, 49-54), a phospholipid, e.g., di-hexadecyl- rac-glycerol or triethylammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651-3654; Shea et al., Nucl. Acids Res., 1990, 18, 3777-3783), a polyamine or a polyethylene glycol chain (Manoharan et al., Nucleosides & Nucleotides, 1995, 14, 969-973), or adamantane acetic acid (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651-3654), a palmityl moiety (Mishra et al., Biochim. Biophys. Acta, 1995, 1264, 229-237), or an octadecylamine or hexylamino-carbonyl- oxycholesterol moiety (Crooke et al., J. Pharmacol. Exp. Ther., 1996, 277, 923-937. A conjugate may include a “Protein Transduction Domain” or PTD (also known as a CPP— cell penetrating peptide), which may refer to a polypeptide, polynucleotide, carbohydrate, or organic or inorganic compound that facilitates traversing a lipid bilayer, micelle, cell membrane, organelle membrane, or vesicle membrane. A PTD attached to another molecule, which can range from a small polar molecule to a large macromolecule and / or a nanoparticle, facilitates the molecule traversing a membrane, for example going from extracellular space to intracellular space, or cytosol to within an organelle. In some embodiments, a PTD is covalently linked to the amino terminus of an exogenous polypeptide (e.g., a site-directed modifying polypeptide). In some embodiments, a PTD is covalently linked to the carboxyl terminus of an exogenous polypeptide (e.g., a site-directed modifying polypeptide). In some embodiments, a PTD is covalently linked to a nucleic acid (e.g., a DNA-targeting RNA, a polynucleotide encoding a DNA-targeting RNA, a polynucleotide encoding a site-directed modifying polypeptide, etc.). In some embodiments, a polynucleotide of the disclosure is codon optimized for expression in a eukaryotic cell. In some embodiments, the polynucleotide sequence encoding a stiCas9 is codon optimized for expression in an animal cell. In some embodiments, the polynucleotide sequence encoding the recombinant Cas protein is codon optimized for expression in a human cell. In some embodiments, the polynucleotide sequence encoding the recombinant Cas protein is codon optimized for expression in a plant cell. Codon optimization is the adjustment of codons to match the expression host’s tRNA abundance in order to increase yield and efficiency of recombinant or heterologous protein expression. Codon optimization methods are routine in the art and may be performed using software programs such as, for example, Integrated DNA Technologies’ Codon Optimization tool, Entelechon’s Codon Usage Table analysis tool, GENEMAKER’s Blue Heron software, Aptagen’s Gene Forge software, DNA Builder Software, General Codon Usage Analysis software, the publicly available OPTIMIZER software, and Genscript’s OptimumGene algorithm. CRISPR-Cas systems In some embodiments, the present disclosure encompasses CRISPR-Cas systems comprising a naturally-occurring Cas protein or a non-naturally occurring Cas protein, and a polynucleotide encoding a sequence of interest. In some embodiments, the CRISPR-Cas system comprises a naturally-occurring Cas protein or non-naturally occurring Cas protein, a polynucleotide encoding a sequence of interest, and a polynucleotide capable of forming a complex with a Cas protein. In some embodiments, the polynucleotide capable of forming a complex with a Cas protein comprises a guide sequence, a Cas-binding region, and a DNA template region. In some embodiments, the CRISPR-Cas system comprises a regulatory element operably linked to a polynucleotide sequence encoding a recombinant Cas protein provided herein, and polynucleotide that forms a complex with the recombinant Cas protein and includes a guide sequence. In some embodiments, the regulatory element linked to the polynucleotide sequence encoding a recombinant Cas protein is a promoter. In some embodiments, the regulatory element is a eukaryote promoter. In some embodiments, the regulatory element is a viral promoter. In some embodiments, the regulatory element is a eukaryotic regulatory element, i.e., a eukaryotic promoter. In some embodiments, the eukaryotic regulatory element is a mammalian promoter. In some embodiments, the polynucleotide capable of forming a complex with the Cas protein of the CRISPR-Cas system is an RNA molecule. An RNA molecule that binds to CRISPR-Cas components and targets them to a specific location within the target DNA is referred to herein as “guide RNA,” “gRNA,” or “small guide RNA” and may also be referred to herein as a “DNA-targeting RNA.” A guide polynucleotide, e.g., guide RNA, includes at least two nucleotide segments: at least one “DNA-binding segment” and at least one “polypeptide-binding segment.” By “segment” is meant a part, section, or region of a molecule, e.g., a contiguous stretch of nucleotides of guide polynucleotide molecule. The definition of “segment,” unless otherwise specifically defined, is not limited to a specific number of total base pairs. In some embodiments, the DNA-binding segment (or “DNA-targeting sequence”) of the guide polynucleotide hybridizes with a target sequence in a cell. In some embodiments, the DNA-binding segment of the guide polynucleotide, e.g., guide RNA, includes a polynucleotide sequence that is complementary to a specific sequence within a target DNA. In some embodiments, the guide polynucleotide of the present disclosure has a guide sequence that hybridizes to a target sequence in a eukaryotic cell. In some embodiments, the eukaryotic cell is an animal or human cell. In some embodiments, the eukaryotic cell is a human or rodent or bovine cell line or cell strain. Examples of such cells, cell lines, or cell strains include, but are not limited to, mouse myeloma (NSO)-cell lines, Chinese hamster ovary (CHO)-cell lines, HT1080, H9, HepG2, MCF7, MDBK Jurkat, NIH3T3, PC12, BHK (baby hamster kidney cell), VERO, SP2 / 0, YB2 / 0, Y0, C127, L cell, COS, e.g., COS1 and COS7, QC1-3, HEK-293, VERO, PER.C6, HeLA, EBl, EB2, EB3, oncolytic or hybridoma-cell lines. In some embodiments, the eukaryotic cells are CHO-cell lines. In some embodiments, the eukaryotic cell is a CHO cell. In some embodiments, the cell is a CHO-K1 cell, a CHO-K1 SV cell, a DG44 CHO cell, a DUXB11 CHO cell, a CHOS, a CHO GS knock-out cell, a CHO FUT8 GS knock-out cell, a CHOZN, or a CHO- derived cell. The CHO GS knock-out cell (e.g., GSKO cell) is, for example, a CHO-K1 SV GS knockout cell. The CHO FUT8 knockout cell is, for example, the POTELLIGENT CHOK1 SV (Lonza Biologics, Inc.). Eukaryotic cells can also be avian cells, cell lines or cell strains, such as, for example, EBX cells, EB14, EB24, EB26, EB66, or EBvl3. In some embodiments, the eukaryotic cell is a human cell. In some embodiments, the human cell is a stem cell. The stem cells can be, for example, pluripotent stem cells, including embryonic stem cells (ESCs), adult stem cells, induced pluripotent stem cells (iPSCs), tissue specific stem cells (e.g., hematopoietic stem cells) and mesenchymal stem cells (MSCs). In some embodiments, the human cell is a differentiated form of any of the cells described herein. In some embodiments, the eukaryotic cell is a cell derived from any primary cell in culture. In some embodiments, the eukaryotic cell is a hepatocyte such as a human hepatocyte, animal hepatocyte, or a non-parenchymal cell. For example, the eukaryotic cell can be a plateable metabolism qualified human hepatocyte, a plateable induction qualified human hepatocyte, plateable human hepatocyte, suspension qualified human hepatocyte (including 10-donor and 20-donor pooled hepatocytes), human hepatic kupffer cells, human hepatic stellate cells, dog hepatocytes (including single and pooled Beagle hepatocytes), mouse hepatocytes (including CD-1 and C57BI / 6 hepatocytes), rat hepatocytes (including Sprague-Dawley, Wistar Han, and Wistar hepatocytes), monkey hepatocytes (including Cynomolgus or Rhesus monkey hepatocytes), cat hepatocytes (including Domestic Shorthair hepatocytes), and rabbit hepatocytes (including New Zealand White hepatocytes). In some embodiments, the eukaryotic cell is a plant cell. For example, the plant cell can be of a crop plant such as cassava, corn, sorghum, wheat, or rice. The plant cell can be of an algae, tree, or vegetable. The plant cell can be of a monocot or dicot or of a crop or grain plant, a production plant, fruit, or vegetable. For example, the plant cell can be of a tree, e.g., a citrus tree such as orange, grapefruit, or lemon tree; peach or nectarine trees; apple or pear trees; nut trees such as almond or walnut or pistachio trees; nightshade plants, e.g., potatoes, plants of the genus Brassica, plants of the genus Lactuca; plants of the genus Spinacia; plants of the genus Capsicum; cotton, tobacco, asparagus, carrot, cabbage, broccoli, cauliflower, tomato, eggplant, pepper, lettuce, spinach, strawberry, blueberry, raspberry, blackberry, grape, coffee, cocoa, etc. In some embodiments, the guide sequence of the guide polynucleotide is about 5 to about 50 nucleotides. In some embodiments, the guide sequence of the guide polynucleotide is about 6 to about 45 nucleotides. In some embodiments, the guide sequence of the guide polynucleotide is about 7 to about 40 nucleotides. In some embodiments, the guide sequence of the guide polynucleotide is about 8 to about 35 nucleotides. In some embodiments, the guide sequence of the guide polynucleotide is about 9 to about 30 nucleotides. In some embodiments, the guide sequence of the guide polynucleotide is about 10 to about 20 nucleotides. In some embodiments, the guide sequence of the guide polynucleotide is about 12 to about 20 nucleotides. In some embodiments, the guide sequence of the guide polynucleotide is about 14 to about 20 nucleotides. In some embodiments, the guide sequence of the guide polynucleotide is about 16 to about 20 nucleotides. In some embodiments, the guide sequence of the guide polynucleotide is about 18 to about 20 nucleotides. In some embodiments, the guide sequence of the guide polynucleotide is about 5 to about 10 nucleotides. In some embodiments, the guide sequence of the guide polynucleotide is about 6 to about 10 nucleotides. In some embodiments, the guide sequence of the guide polynucleotide is about 7 to about 10 nucleotides. In some embodiments, the guide sequence of the guide polynucleotide is about 8 to about 10 nucleotides. The length of the guide sequence may be determined by the skilled artisan using guide sequence design tools such as, e.g., CRISPR Design Tool (Hsu et al., Nat Biotechnol 31(9):827-832 (2013)), ampliCan (Labun et al., bioRxiv 2018, doi: 10.1101 / 249474), CasFinder (Alach et al., bioRxiv 2014, doi: 10.1101 / 005074), CHOPCHOP (Labun et al., Nucleic Acids Res 2016, doi: 10.1093 / nar / gkw398), and the like. In some embodiments, the guide polynucleotide, e.g., guide RNA, of the present disclosure includes a polypeptide-binding sequence / segment. The polypeptide-binding segment (or “protein-binding sequence”) of the guide polynucleotide, e.g., guide RNA, interacts with the polynucleotide-binding domain of a Cas protein of the present disclosure. Such polypeptide-binding segments or sequences are known to those of skill in the art, e.g., those disclosed in U.S. Patent Publications 2014 / 0068797, 2014 / 0273037, 2014 / 0273226, 2014 / 0295556, 2014 / 0295557, 2014 / 0349405, 2015 / 0045546, 2015 / 0071898, 2015 / 0071899, and 2015 / 0071906, the disclosures of which are incorporated herein in their entireties. In some embodiments, the polypeptide-binding segment of the guide polynucleotide binds to Cas9. In some embodiments, the polypeptide-binding segment of the guide polynucleotide binds to the recombinant Cas9 proteins provided herein. In some embodiments, the guide polynucleotide is at least about 10, 15, 20, 25 or 30 nucleotides and up to about 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140 or 150 nucleotides. In some embodiments, the guide polynucleotide is between about 10 to about 150 nucleotides. In some embodiments, the guide polynucleotide is between about 20 to about 120 nucleotides. In some embodiments, the guide polynucleotide is between about 30 to about 100 nucleotides. In some embodiments, the guide polynucleotide is between about 40 to about 80 nucleotides. In some embodiments, the guide polynucleotide is between about 50 to about 60 nucleotides. In some embodiments, the guide polynucleotide is between about 10 to about 35 nucleotides. In some embodiments, the guide polynucleotide is between about 15 to about 30 nucleotides. In some embodiments, the guide polynucleotide is between about 20 to about 25 nucleotides. The guide polynucleotide, e.g., guide RNA, can be introduced into the target cell as an isolated molecule, e.g., RNA molecule, or is introduced into the cell using an expression vector containing DNA encoding the guide polynucleotide, e.g., guide RNA. In some embodiments, the guide polynucleotide of the CRISPR-Cas system is linked to a direct repeat sequence. A direct repeat, or DR, sequence is an array of repetitive sequences in the CRISPR locus, interspaced by short stretches of non-repetitive sequences (spacers). The spacer sequences target the Protospacer Adjacent Motifs (PAM) on the target sequence. When the non-coding portion of the CRISPR locus (i.e., the guide polynucleotide and the tracrRNA) is transcribed, the transcript is cleaved at the DR sequences into short crRNAs containing individual spacer sequences, which direct the Cas9 nuclease to the PAM. In some embodiments, the DR sequence is RNA. In some embodiments, the DR sequence is encoded by a nucleic acid. In some embodiments, the DR sequence is linked to the guide polynucleotide. In some embodiments, the DR sequence is linked to the guide sequence of the guide polynucleotide. In some embodiments, the DR sequence includes a secondary structure. In some embodiments, the DR sequence includes a stem loop structure. In some embodiments, the DR sequence is 10 to 20 nucleotides. In some embodiments, the DR sequence is at least 16 nucleotides. In some embodiments, the DR sequence is at least 16 nucleotides and includes a single stem loop. In some embodiments, the DR sequence includes an RNA aptamer. In some embodiments, the secondary structure or stem loop in the DR is the recognized by a nuclease for cleavage. In some embodiments, the nuclease is a ribonuclease. In some embodiments, the nuclease is RNase III. In some embodiments, the CRISPR-Cas systems of the present disclosure further include a tracrRNA. A “tracrRNA,” or trans-activating CRISPR-RNA, forms an RNA duplex with a pre-crRNA, or pre-CRISPR-RNA, and is then cleaved by the RNA-specific ribonuclease RNase III to form a crRNA / tracrRNA hybrid. In some embodiments, the guide RNA includes the crRNA / tracrRNA hybrid. In some embodiments, the tracrRNA component of the guide RNA activates the Cas protein. In some embodiments, the guide polynucleotide of the CRISPR-Cas system includes a tracrRNA sequence. In some embodiments, the CRISPR-Cas system includes a separate polynucleotide including a tracrRNA sequence. In some embodiments, the polynucleotide encoding a recombinant Cas protein and a guide polynucleotide is on a single vector. In some embodiments, the polynucleotide encoding a recombinant Cas protein, a guide polynucleotide (or nucleotide that can be transcribed into a guide polynucleotide), and a tracrRNA are on a single vector. In some embodiments, the polynucleotide encoding a recombinant Cas protein, a guide polynucleotide (or nucleotide that can be transcribed into a guide polynucleotide), a tracrRNA, and a direct repeat sequence are on a single vector. In some embodiments, the vector is an expression vector. In some embodiments, the vector is a mammalian expression vector. In some embodiments, the vector is a human expression vector. In some embodiments, the vector is a plant expression vector. In some embodiments, the polynucleotide encoding a recombinant Cas protein and a guide polynucleotide is a single nucleic acid molecule. In some embodiments, the polynucleotide encoding a recombinant Cas protein, a guide polynucleotide, and a tracrRNA is a single nucleic acid molecule. In some embodiments, the polynucleotide encoding a recombinant Cas protein, a guide polynucleotide, a tracrRNA, and a direct repeat sequence is a single nucleic acid molecule. In some embodiments, the single nucleic acid molecule is an expression vector. In some embodiments, the single nucleic acid molecule is a mammalian expression vector. In some embodiments, the single nucleic acid molecule is a human expression vector. In some embodiments, the single nucleic acid molecule is a plant expression vector. In some embodiments, the recombinant Cas protein and the guide polynucleotide are capable of forming a complex. In some embodiments, the complex of the recombinant Cas protein and the guide polynucleotide does not occur in nature. Cells In some embodiments, the eukaryotic cell is an animal or human cell. In some embodiments, the eukaryotic cell is a human or rodent or bovine cell line or cell strain. Examples of such cells, cell lines, or cell strains include, but are not limited to, mouse myeloma (NSO)-cell lines, Chinese hamster ovary (CHO)-cell lines, HT1080, H9, HepG2, MCF7, MDBK Jurkat, NIH3T3, PC12, BHK (baby hamster kidney cell), VERO, SP2 / 0, YB2 / 0, Y0, C127, L cell, COS, e.g., COS1 and COS7, QC1-3, HEK-293, VERO, PER.C6, HeLa, EBl, EB2, EB3, oncolytic or hybridoma-cell lines. In some embodiments, the eukaryotic cells are CHO-cell lines. In some embodiments, the eukaryotic cell is a CHO cell. In some embodiments, the cell is a CHO-K1 cell, a CHO-K1 SV cell, a DG44 CHO cell, a DUXB11 CHO cell, a CHOS, a CHO GS knock-out cell, a CHO FUT8 GS knock- out cell, a CHOZN, or a CHO-derived cell. The CHO GS knock-out cell (e.g., GSKO cell) is, for example, a CHO-K1 SV GS knockout cell. The CHO FUT8 knockout cell is, for example, the POTELLIGENT CHOK1 SV (Lonza Biologics, Inc.). Eukaryotic cells can also be avian cells, cell lines or cell strains, such as, for example, EBX cells, EB14, EB24, EB26, EB66, or EBvl3. In some embodiments, the eukaryotic cell is a human cell. In some embodiments, the human cell is a stem cell. The stem cells can be, for example, pluripotent stem cells, including embryonic stem cells (ESCs), adult stem cells, induced pluripotent stem cells (iPSCs), tissue specific stem cells (e.g., hematopoietic stem cells) and mesenchymal stem cells (MSCs). In some embodiments, the cell is a pluripotent stem cell. In some embodiments, the cell is an induced pluripotent stem cell. In some embodiments, the human cell is a differentiated form of any of the cells described herein. In some embodiments, the eukaryotic cell is a cell derived from any primary cell in culture. In some embodiments, the eukaryotic cell is a hepatocyte such as a human hepatocyte, animal hepatocyte, or a non-parenchymal cell. For example, the eukaryotic cell can be a plateable metabolism qualified human hepatocyte, a plateable induction qualified human hepatocyte, plateable human hepatocyte, suspension qualified human hepatocyte (including 10-donor and 20-donor pooled hepatocytes), human hepatic kupffer cells, human hepatic stellate cells, dog hepatocytes (including single and pooled Beagle hepatocytes), mouse hepatocytes (including CD-1 and C57BI / 6 hepatocytes), rat hepatocytes (including Sprague-Dawley, Wistar Han, and Wistar hepatocytes), monkey hepatocytes (including Cynomolgus or Rhesus monkey hepatocytes), cat hepatocytes (including Domestic Shorthair hepatocytes), and rabbit hepatocytes (including New Zealand White hepatocytes). In some embodiments, the eukaryotic cell is a hematopoietic cell. In some embodiments, the hematopoietic cell is a myeloid progenitor cell. In some embodiments, the hematopoietic cell is a lymphoid progenitor cell. In some embodiments, the hematopoietic cell is a mast cell, a megakarytocyte, a thrombocyte, basophil, a neutrophil, an eosinophil, a dendritic cell, a monocyte, or a macrophage. In some embodiments, the hematopoietic cell is a natural killer cell (NK cell), a T lymphocyte, or a B lymphocyte. In some embodiments, the T or B lymphocyte comprises a chimeric antigen receptor (CAR). In some embodiments, the eukaryotic cell is a plant cell. For example, the plant cell can be of a crop plant such as cassava, corn, sorghum, wheat, or rice. The plant cell can be of an algae, tree, or vegetable. The plant cell can be of a monocot or dicot or of a crop or grain plant, a production plant, fruit, or vegetable. For example, the plant cell can be of a tree, e.g., a citrus tree such as orange, grapefruit, or lemon tree; peach or nectarine trees; apple or pear trees; nut trees such as almond or walnut or pistachio trees; nightshade plants, e.g., potatoes, plants of the genus Brassica, plants of the genus Lactuca; plants of the genus Spinacia; plants of the genus Capsicum; cotton, tobacco, asparagus, carrot, cabbage, broccoli, cauliflower, tomato, eggplant, pepper, lettuce, spinach, strawberry, blueberry, raspberry, blackberry, grape, coffee, cocoa, etc. In some embodiments, the eukaryotic cell is a tissue culture of any of the aforementioned cells. In some embodiments, the eukaryotic cell is in the form of a tissue extract of any of the aforementioned cells. In some embodiments, the eukaryotic cell comprises a genomically-integrated Cas polynucleotide. In some embodiments, the eukaryotic cell comprises an inducible genomically-integrated Cas polynucleotide. Delivery systems Various methods are known in the art for delivery of CRISPR-Cas systems. Suitable delivery systems include microinjection, electroporation, transfection, or hydrodynamic delivery of a polynucleotide encoding a Cas protein, a polynucleotide comprising a sequence of interest, and / or a polynucleotide capable of forming a complex with a Cas protein. In some embodiments, the delivery system comprises a delivery particle. Examples of such delivery systems, including nanoparticles, cell-penetrating peptides, and DNA nanoclews, are disclosed in Lino et al., Drug Delivery, 25(1):1234-1257 (2018)). In some embodiments, the CRISPR-Cas system, including a Cas protein, a polynucleotide encoding a Cas protein, a polynucleotide encoding a sequence of interest, and / or a polynucleotide capable of forming a complex with a Cas protein, of the present disclosure is delivered by a delivery particle. A delivery particle is a biological delivery system or formulation which includes a particle. A “particle,” as defined herein, is an entity having a maximum diameter of about 100 microns (μm). In some embodiments, the particle has a maximum diameter of about 10 μm. In some embodiments, the particle has a maximum diameter of about 2000 nanometers (nm). In some embodiments, the particle has a maximum diameter of about 1000 nm. In some embodiments, the particle has a maximum diameter of about 900 nm, about 800 nm, about 700 nm, about 600 nm, about 500 nm, about 400 nm, about 300 nm, about 200 nm, or about 100 nm. In some embodiments, the particle has a diameter of about 25 nm to about 200 nm. In some embodiments, the particle has a diameter of about 50 nm to about 150 nm. In some embodiments, the particle has a diameter of about 75 nm to about 100 nm. Delivery particles may be provided in any form, including but not limited to: solid, semi- solid, emulsion, or colloidal particles. In some embodiments, the delivery particle is a lipid- based system, a liposome, a micelle, a microvesicle, an exosome, or a gene gun. In some embodiments, the delivery particle includes a CRISPR-Cas system. In some embodiments, the delivery particle includes a CRISPR-Cas system including a recombinant Cas protein and a polynucleotide capable of forming a complex with the Cas protein, wherein said polynucleotide comprises a guide polynucleotide. In some embodiments, the delivery particle includes a Cas protein, a polynucleotide comprising a sequence of interest, and a polynucleotide capable of forming a complex with a Cas protein and comprising a guide polynucleotide. In some embodiments, the delivery particle includes a CRISPR-Cas system including a recombinant Cas protein and a polynucleotide which forms a complex with a Cas protein and which comprises a guide polynucleotide, wherein the recombinant Cas protein and the polynucleotide are in a complex. In some embodiments, the delivery particle includes a CRISPR-Cas system including a recombinant Cas protein, a polynucleotide which forms a complex with a Cas protein and which comprises a guide polynucleotide, and polynucleotide including a tracrRNA. In some embodiments, the delivery particle includes a CRISPR-Cas system including a Cas protein, a polynucleotide which forms a complex with a Cas protein and comprises a guide polynucleotide, and a tracrRNA. In some embodiments, the complex of the Cas protein and a polynucleotide of the disclosure is a ribonucleoprotein (RNP), wherein said RNP is delivered via hydrodynamic delivery, a nanoparticle, a vesicle, a cell-penetrating peptide, or a DNA nanoclew. In some embodiments, the delivery particle further includes a lipid, a sugar, a metal or a protein. In some embodiments, the delivery particle is a lipid envelope. Delivery of mRNA using lipid envelopes or delivery particles including lipids is described, for example, in Su et al., Molecular Pharmacology 8(3):774-784 (2011). In some embodiments, the delivery particle is a sugar-based particle, for example, GalNAc. Sugar-based particles are described in WO 2014 / 118272 and Nair et al., J. Am. Chem. Soc.136(49):16958-16961 (2014). In some embodiments, the delivery particle is a nanoparticle. Nanoparticles encompassed in the present disclosure may be provided in different forms, e.g., as solid nanoparticles (e.g., metal such as silver, gold, iron, titanium), non-metal, lipid-based solids, polymers, suspensions of nanoparticles, or combinations thereof. Metal, dielectric, and semiconductor nanoparticles may be prepared, as well as hybrid structures (e.g., core-shell nanoparticles). Nanoparticles made of semiconducting material may also be labeled quantum dots if they are small enough (typically sub 10 nm) that quantization of electronic energy levels occurs. Such nanoscale particles are used in biomedical applications as drug carriers or imaging agents and may be adapted for similar purposes in the present disclosure. Preparation of delivery particles is further described in U.S. Patent Publications 2011 / 0293703, 2012 / 0251560, and 2013 / 0302401; and U.S. Patent Nos. 5,543,158, 5,855,913, 5,895,309, 6,007,845, and 8,709,843. In some embodiments, a vesicle includes the CRISPR-Cas system of the present disclosure. A “vesicle” is a small structure within a cell having a fluid enclosed by a lipid bilayer. In some embodiments, the CRISPR-Cas system of the present disclosure is delivered by a vesicle. In some embodiments, the vesicle includes a recombinant Cas protein and a guide polynucleotide. In some embodiments, the vesicle includes a Cas protein and a guide polynucleotide, wherein the Cas protein and the guide polynucleotide are in a complex. In some embodiments, the vesicle includes a CRISPR-Cas system including a Cas protein, a polynucleotide capable of forming a complex with a Cas protein and comprising a guide polynucleotide, and a polynucleotide including a tracrRNA. In some embodiments, the vesicle includes a CRISPR-Cas system including a t Cas protein, a polynucleotide capable of forming a complex with a Cas protein and comprising guide polynucleotide, and a tracrRNA. In some embodiments, the vesicle including the Cas protein and polynucleotide capable of forming a complex with the Cas protein and comprising a guide polynucleotide is an exosome or a liposome. In some embodiments, the vesicle is an exosome. In some embodiments, the exosome is used to deliver the CRISPR-Cas systems of the present disclosure. Exosomes are endogenous nano-vesicles (i.e., having a diameter of about 30 to about 100 nm) that transport RNAs and proteins, and which can deliver RNA to the brain and other target organs. Engineered exosomes for delivery of exogenous biological materials into target organs is described, for example, by Alvarez-Erviti et al., Nature Biotechnology 29:341 (2011), El-Andaloussi et al., Nature Protocols 7:2112-2116 (2012), and Wahlgren et al., Nucleic Acids Research 40(17):e130 (2012). In some embodiments, the liposome is used to deliver the CRISPR-Cas systems of the present disclosure. Liposomes are spherical vesicle structures having at least one lipid bilayer and can be used as a vehicle for administration of nutrients and pharmaceutical drugs. Liposomes are often composed of phospholipids, in particular phosphatidylcholine, but also other lipids such as egg phosphatidylethanolamine. Types of liposomes include, but are not limited to, multilamellar vesicle, small unilamellar vesicle, large unilamellar vesicle, and cochleate vesicle. See, e.g., Spuch and Navarro, Journal of Drug Delivery, Article ID 469679 (2011). Liposomes for delivery of biological materials such as CRISPR- Cas components are described, for example, by Morrissey et al., Nature Biotechnology 23(8):1002-1007 (2005), Zimmerman et al., Nature Letters 441:111-114 (2006), and Li et al., Gene Therapy 19:775-780 (2012). In some embodiments, the Cas protein can be delivered using cell-penetrating peptide fused to the Cas protein. In some embodiments, the Cas protein and a polynucleotide of the disclosure can be delivered in the form of a DNA nanoclew. DNA nanoclews are spherical structures comprising DNA that can be loaded with a payload, such as a Cas protein (Sun et al., J. Am. Chem. Soc., 136:14722-14725). DNA nanoclews have been used in vitro for delivery of Cas9 editing systems (Lino et al., Drug Delivery, 25(1):1234-1257). In some embodiments, a viral vector includes the CRISPR-Cas systems of the present disclosure. In some embodiments, the CRISPR-Cas system of the present disclosure is delivered by a viral vector. In some embodiments, the viral vector includes a recombinant Cas9 and a guide polynucleotide. In some embodiments, the viral vector includes a Cas protein and a guide polynucleotide, wherein the Cas protein and the guide polynucleotide are in a complex. In some embodiments, the viral vector includes a CRISPR-Cas system including a Cas protein, a polynucleotide capable of forming a complex with a Cas protein and comprising a guide polynucleotide, and a polynucleotide including a tracrRNA. In some embodiments, the viral vector includes a CRISPR-Cas system including a Cas protein, a polynucleotide capable of forming a complex with a Cas protein and comprising a guide polynucleotide, and a tracrRNA. In some embodiments, the viral vector is of a retrovirus, a lentivirus, an adenovirus, or an adeno-associated virus. Examples of viral vectors are provided herein. In some embodiments, retroviral, lentiviral, adenoviral, and / or adeno-associated virus (AAV) vectors can be used as a viral vector including the elements of the CRISPR-Cas systems as described herein. In some embodiments of the present disclosure, the Cas protein is expressed intracellularly by cells transduced by a viral vector. In some embodiments, the Cas proteins and methods of the present disclosure are used in ex vivo gene editing, such as CAR-T type therapies. These embodiments may involve modification of cells from human donors. In these instances, viral vectors can be also used; however, there is the additional option to directly transfect the Cas9 protein (along with in vitro transcribed guide RNA and donor DNA) into cultured cells. Inhibitors or modulators of Artemis As used herein, an inhibitor or modulator of Artemis is any compound, molecule, or entity that inhibits, antagonizes, blocks, or decreases the activity and / or level of any component of Artemis. The Artemis inhibitor can be an antibody or antigen-binding fragment thereof, a peptide, soluble protein, siRNA, antisense oligonucleotide, aptamer, or small-molecule compound that inhibits, antagonizes, blocks, or decreases the activity and / or level of any component of Artemis. In some embodiments, the inhibitor or modulator of Artemis decreases the activity of Artemis by at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%. In some embodiments the inhibitor is a metal chelator, e.g. N,N,N′,N′-tetrakis(2- pyridinylmethyl)-1,2-ethanediamine and Tris(2-pyridylmethyl) amine. In some embodiments, the inhibitor or modulator of Artemis is a beta-lactam antibiotic. beta-lactam antibiotics are antibiotics that contain a beta-lactam ring in their chemical structure. This includes penicillin derivatives (penams), cephalosporins and cephamycins (cephems), monobactams, carbapenems and carbacephems. Examples of beta lactam antibiotics which have been shown to be effective as inhibitors or modulators of Artimis are Ebselen, Ceftriaxone, disulfiram , auranofin Yosaatmadja et al. in Nucleic Acids Research, 49(16): 9310–9326 (2021), ampicillin, SBI-713 Li et al. in JBC 289, (11): 7825- 7834 ( 2014). Further suitable examples are clavulanic acid, aztronam, boric acid, phenylboronic acid, m-aminophenylboronate, 2-formylphenylboronate, 4- formylphenylboronate, 4-methylphenylboronate, tetraphenylboronic acid, m- (dansylamidophenyl)-boronic acid, (1R)-1-acetamido-2-(3-carboxyphenyl) ethane boronic acid. In some embodiments, the inhibitor or modulator of Artemis is a small molecule HSP70 Agonists such as N-hydroxychromane-2-carboxamide and derivatives. In some embodiments, the inhibitor or modulator of Artemis is a PROTAC. As used herein, a proteolysis-targeting chimera (PROTAC) refers to a bifunctional small molecule comprising: (i) a target-binding ligand configured to engage a selected protein of interest; (ii) an E3 ubiquitin ligase–recruiting ligand configured to bind an endogenous E3 ligase; and (iii) a linker that operably connects the two ligands to enable formation of a ternary complex between the target protein and the E3 ligase. In the context of the present disclosure, PROTACs function as inhibitors or modulators of protein activity and protein expression by catalyzing ubiquitination of the engaged target protein, thereby directing its proteasome-dependent degradation. By reducing cellular abundance of the target rather than solely occupying an active site, PROTACs can provide event-driven, sustained attenuation of target-dependent signaling, scaffolding, or enzymatic functions. It is known in the art that degradation performance is influenced by target and ligase affinity, linker length and composition, ternary complex cooperativity, and cellular proteostasis factors. In one embodiment, reversible target engagement allows temporal control of degradation upon compound removal. In some embodiments, the inhibitor or modulator of Artemis is a molecular glue. As used herein, a molecular glue refers to a monovalent small molecule that promotes or stabilizes a protein–protein interaction between a target protein and an endogenous effector, such as an E3 ubiquitin ligase or other regulatory factor, without requiring a bifunctional architecture. In the context of the present disclosure, molecular glues act as inhibitors or modulators of protein activity and protein expression by enhancing proximity between the target and the effector to induce ubiquitination and proteasome-mediated degradation, or by stabilizing nonproductive complexes that diminish catalytic output, partner binding, or subcellular localization of the target. It is known in the art that molecular glues can alter apparent substrate specificity of an E3 ligase by inducing or stabilizing neomorphic interaction surfaces, thereby enabling selective recruitment and degradation of defined targets. In one embodiment, a molecular glue decreases steady-state target protein levels to suppress pathway activity; in another embodiment, it modulates target function without degradation by enforcing inhibitory complex formation. In some embodiments the inhibitor or modulator is a gene silencing system, for example a CRISPER based silencing system. As used herein, a CRISPR-based silencing system refers to a programmable nucleic acid–directed complex that attenuates gene expression without requiring targeted double-strand DNA cleavage. In the context of the present disclosure, such a system typically comprises a catalytically inactive or nickase variant of a CRISPR- associated nuclease (e.g., dCas9 or dCas12) operably linked to one or more transcriptional repressor domains and guided by a CRISPR RNA or single-guide RNA to a defined genomic locus to impede transcription initiation or elongation. It is known in the art that recruitment of repressive effectors (for example, KRAB or related domains) and strategic placement of guide sequences within promoter or enhancer regions can effect transcriptional downregulation with locus and strand specificity. In one embodiment, the system is configured for reversible, tunable repression under inducible control. In some embodiments, the inhibitor or modulator of Artemis is selected from an Artemis dominant-negative peptide, an siRNA, an shRNA, a miRNA, or an antisense DNA or RNA.. As used herein, a dominant-negative variant refers to a Artemis variant that, when expressed or introduced into a cell, interferes with the activity of an endogenous wild-type protein by forming nonfunctional complexes or by competitively occupying binding interfaces, cofactors, or subcellular sites required for normal function. In the context of the present disclosure, dominant-negative peptides may retain interaction motifs while lacking catalytic activity or proper conformational dynamics, thereby attenuating native protein function at the protein–protein interaction level rather than by altering gene expression. It is known in the art that dominant-negative inhibition can be achieved through oligomerization-defective mutants, catalytically inactive variants, or truncations that preserve binding but abrogate productive signalling. In one embodiment, a dominant- negative peptide includes an engineered destabilization or localization sequence to modulate potency and duration of inhibition. In some embodimetns the dominant-negative variant has 99 % sequence identity with SE ID. As used herein, siRNA (small interfering RNA) denotes a double-stranded RNA of typically 19–23 base pairs with 2-nucleotide 3′ overhangs that, upon cellular uptake, is incorporated into an Argonaute-containing RNA-induced silencing complex to direct sequence-specific cleavage or degradation of complementary target mRNA. In the context of the present disclosure, siRNAs function as post-transcriptional modulators of protein expression by reducing the abundance of the corresponding transcript. It is known in the art that chemical modifications (e.g., 2′-O-alkyl, 2′-F, phosphorothioate linkages) and duplex design (guide / passenger asymmetry, seed optimization) influence stability, potency, and specificity. In one embodiment, siRNAs are formulated with delivery vehicles to achieve transient and tunable inhibition of protein production. As used herein, shRNA (short hairpin RNA) refers to a single RNA transcript comprising a sense and antisense region separated by a loop sequence that folds into a stem–loop structure and is processed intracellularly, typically by Dicer, to yield an siRNA-like guide strand capable of directing RISC-mediated silencing of a target mRNA. In the context of the present disclosure, shRNAs are expressed from plasmid or viral vectors under RNA polymerase II or III promoters to provide sustained knockdown of protein expression. It is known in the art that promoter choice, copy number, and hairpin architecture (stem length, loop composition) modulate silencing efficiency and durability. In one embodiment, inducible shRNA expression systems are employed to enable temporal control of inhibition. As used herein, miRNA (microRNA) denotes an endogenous or engineered small RNA that guides Argonaute-mediated repression of target transcripts through partial complementarity, resulting in translational inhibition and / or mRNA destabilization. In the context of the present disclosure, miRNA mimics or expression cassettes are used to modulate protein output from one or multiple genes bearing cognate seed-matched sites within untranslated or coding regions. It is known in the art that miRNAs can exert broad network-level effects due to multi-target engagement and that context-dependent factors, including site accessibility and cooperative binding, influence efficacy. In one embodiment, synthetic miRNA mimics or tough decoy constructs are utilized to enhance or sequester specific miRNA activities to achieve the desired modulation of protein function. As used herein, antisense DNA or RNA refers to a single-stranded oligonucleotide designed to hybridize in a sequence-specific manner to a target RNA (e.g., pre-mRNA or mRNA) to alter its processing, stability, or translation and thereby reduce or modify the production of the encoded protein. In the context of the present disclosure, antisense oligonucleotides may operate via RNase H–mediated degradation of RNA in RNA:DNA hybrids or via steric blockade to inhibit ribosome progression or spliceosome assembly, resulting in diminished protein levels or altered isoform expression. It is known in the art that backbone, sugar, and base modifications (including phosphorothioate, 2′-O-methoxyethyl, LNA, and others) are selected to achieve desired pharmacological and biophysical properties. In one embodiment, splice-switching antisense oligonucleotides are employed to redirect exon usage and thereby modulate protein structure and function without changing genomic DNA. In some embodiments, the inhibitor or modulator of Artemis is an antisense oligonucleotide. As used herein, the term antisense oligonucleotide (ASO) or an antisense oligonucleotide system refers to a synthetic, typically single‑stranded oligomer of nucleic acids configured to hybridize in a sequence‑specific manner to a target RNA, such as a messenger RNA (mRNA), to modulate its processing, stability, or translation. In the context of the present disclosure, ASOs comprise natural or chemically modified nucleotides and internucleoside linkages selected to confer desired hybridization affinity, nuclease resistance, and pharmacokinetic properties. It is known in the art that ASO mechanisms of action include, without limitation, recruitment of RNase H to direct target RNA cleavage, steric blockade of ribosomal or spliceosomal machinery, and alteration of splicing to promote exon inclusion or skipping. In one embodiment, an ASO is designed to bind a selected region of a target mRNA encoding Artemis protein to reduce expression of the corresponding Artemis protein in cells or in a subject. In some embodiments the ASO is selected from an ASO that targets the murine Artemis protein. In some embodiments the ASO is selected from an ASO having SEQ ID NOs 57- 118. In another embodiment the ASO is selected from an ASO that targets the murine Artemis protein. In some embodiments the ASO is selected from an ASO having the SEQ ID NOs 119-173. In some embodiments, the concentration of the inhibitor or modulator of Artemis is 0.01 ^M to about 1 ^M, about 0.1 ^M to about 1 ^M, about 0.1 ^M to about 0.5 ^M, about 0.1 ^M to about 100 ^M, or about 1 ^M to about 50 ^M. In some embodiments, the inhibitor or modulator of Artemis is added to the composition comprising the eukaryotic cell about 0 minutes to about 96 hours before the Cas protein is added, about 0 minutes to about 72 hours before the Cas protein is added, about 0 minutes to about 48 hours before the Cas protein is added, about 0 minutes to about 36 hours before the Cas protein is added, about 0 minutes to about 24 hours before the Cas protein is added, about 0 minutes to about 18 hours before the Cas protein is added, about 0 minutes to about 12 hours before the Cas protein is added, about 0 minutes to about 6 hours before the Cas protein is added, about 0 minutes to about 3 hours before the Cas protein is added, about 0 minutes to about 2 hours before the Cas protein is added, about 0 minutes to about 1 hour before the Cas protein is added, or about 0 minutes to about 30 minutes before the Cas protein is added. In some embodiments, the inhibitor or modulator of Artemis is added to the composition comprising a eukaryotic cell about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 hours before the Cas protein is added. In some embodiments, the inhibitor or modulator of Artemis is added to the composition comprising a eukaryotic cell at the same time the Cas protein is added. In some embodiments, the inhibitor or modulator of Artemis is added to the composition comprising a eukaryotic cell about 0 minutes to about 30 minutes after the Cas protein is added, about 0 minutes to about 1 hour after the Cas protein is added, about 0 minutes to about 3 hours after the Cas protein is added, about 0 minutes to about 6 hours after the Cas protein is added, about 0 minutes to about 12 hours after the Cas protein is added, about 0 minutes to about 18 hours after the Cas protein is added, about 0 minutes to about 24 hours after the Cas protein is added, about 0 minutes to about 36 hours after the Cas protein is added, about 0 minutes to about 48 hours after the Cas protein is added, about 0 minutes to about 72 hours after the Cas protein is added, or about 0 minutes to about 96 hours after the Cas protein is added. In some embodiments, the inhibitor or modulator of Artemis is added to the composition comprising a eukaryotic cell about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 hours after the Cas protein is added. In some embodiments, the inhibitor or modulator of Artemis is in the composition comprising a eukaryotic cell for about 1 to about 300 hours, about 10 to about 200 hours, about 10 to about 100 hours, about 20 to about 80 hours, about 30 to about 70 hours, or about 40 to about hours. In some embodiments, the inhibitor or modulator of Artemis is in the composition comprising a eukaryotic cell for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, 275, or 300 hours. In some embodiments, the inhibitor or modulator of Artemis is added to the composition comprising a eukaryotic cell at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 or more times. All references cited herein, including patents, patent applications, papers, textbooks and the like, and the references cited therein, to the extent that they are not already, are hereby incorporated herein by reference in their entirety. As used herein, the term protein tagging refers to a molecular biology technique in which a defined label, or tag, is operably fused to a protein of interest to facilitate detection, purification, or functional analysis in a cellular or acellular context. In the context of the present disclosure, the tag may comprise a short peptide epitope or a larger polypeptide domain that is genetically linked to the target protein at the Nterminus, Cterminus, or an internal permissive site, provided that the fusion preserves the intended activity or localization of the target protein. It is known in the art that suitable tags include, without limitation, polyhistidine (His), glutathione Stransferase (GST), SNAP, and Halo domains, as well as fluorescent proteins, epitope tags (e.g., FLAG, HA, Myc), and enzymatic reporters. As used herein, a fusion protein denotes a single polypeptide comprising the target protein sequence contiguous with the tag sequence, optionally separated by a linker configured to modulate flexibility, spacing, or protease accessibility. In one embodiment, the fusion protein is produced by expressing a recombinant nucleotide sequence encoding the tag and target protein in operable frame, such that the tag serves as a marker or affinity handle under physiological or assay conditions. In another embodiment, endogenous protein tagging is achieved by genome editing to introduce a tag-encoding sequence at a specified locus, enabling expression under native regulatory control. In the context of the present disclosure, protein tagging supports multiple applications that are known in the art. In one embodiment, affinity tags such as His or GST enable purification of the tagged protein from complex mixtures using immobilized metal affinity chromatography or glutathione affinity systems when antigen-specific antibodies are unavailable or impractical. In another embodiment, fluorescent or luminescent tags permit visualization of subcellular localization (e.g., nuclear, cytoplasmic, membrane-associated) and longitudinal tracking of protein dynamics by live-cell or fixed-cell imaging. In a further embodiment, interaction analyses are performed using tagged bait proteins to capture or report on binding partners, thereby facilitating delineation of signaling pathways and multiprotein complexes. In one embodiment, reporter tags provide readouts of gene expression, proteostasis, or regulated degradation, including use in transcriptional or proteolysis-targeting assays. In another embodiment, endogenous tagging supports structural biology workflows, including preparation of homogeneous protein complexes suitable for high-resolution methods such as cryo-electron microscopy. As used herein, selection of a tag, linker, and placement is made with consideration of the target protein’s structure, function, and intended assay, and may include codon optimization, protease site removal, or incorporation of cleavage sites to enable tag removal post-purification if desired. In one embodiment, tags are employed in conjunction with orthogonal detection reagents (e.g., anti-epitope antibodies, fluorescent ligands, or substrate analogs) to provide quantitative and reproducible measurements. It is known in the art that appropriate controls, including untagged comparators and alternative tag orientations, are useful to confirm that observed properties reflect those of the native protein. In view of the foregoing, protein tagging constitutes a versatile tool to interrogate protein function, localization, interactions, and structure in systems ranging from basic research to translational discovery. EXAMPLES The present disclosure may be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present disclosure and are not intended to limit the disclosure. Example 1. Schematic representation of the role of Artemis on PRINS-mediated insertion. A. This drawing depicts the homology-independent springRNA design. Each springRNA has at the 5’ end a spacer sequence specific to a target site, and the scaffold sequence recognize by the Cas9 enzyme. In the 3’ extension of each springRNA there is a primer binding site (PBS) for the reverse-transcriptase (RT) to initiate reverse transcription of the desired insert included after the PBS., The resulting 3’ overhang generated by the RT would require NHEJ activity to incorporate the insert into the genome. B. This drawing depicts the 4 steps of PRINS. Step 1: The Cas9-reverse transcriptase fusion enzyme binds to the springRNA, and causes a double stranded break at the location in the genome specified by the spacer sequence. Step 2: The reverse transcriptase fused to Cas9 synthesizes a DNA overhang from the template provided by the springRNA. Step 3: The cellular DNA repair factors re-ligates the double stranded break and fills-in the overhang into a double stranded DNA. Step 4: The double stranded break is fully repaired . C. This drawing depicts how Artemis is involved in DNA repair during PRINS editing and how its inhibition or deletion improves the editing outcome. Artemis is recruited to the double stranded break by DNA- PK where it partially degrades the 3’ DNA overhang generated by PRINS editing. Removing or deleting Artemis leads to protection of the 3’ DNA overhang, increasing average insertion length of the overhang and increasing integration rate of the desired insert sequence Example 2. Effect of DCLRE1C (Artemis) gene knockout on the average length of insertion by PRINS editing. The editing efficacy of PRINS in the presence and in the absence of Artemis was evaluated in WT (wild type) and DCLRE1C knockout cells of three different human cell backgrounds (HAP1, HEK293T, iPSC). For testing Artemis effect in the HAP1 background DCLRE1C knockout cell line (Horizon # HZGHC000429c006) and parental cell line (WT HAP1) (Horizon # C631) were used. Artemis DCLRE1C knockout pools in HEK293T and iPSCs (J-line) were generated by spCas9 editing using a pooled three sgRNA approach (Synthego, CRISPR Gene Knockout Kit from EditCo Bio). Spacer sequences used were: 1) 5’- UCACUCACCUUUGUGGCAGU-3’, 2) 5’-CUCCCUAUCGAAGCGGUCUA-3’, and 3) 5’-CGGCGCUAUGAGUUCUUUCG-3’. Briefly, RNP complexes were made by mixing equimolar spCas9 protein (IDT, Alt-R™ S.p. Cas9 Nuclease V3) and pooled sgRNAs and transfected into cells lines by Nucleofection (Lonza). For control, cell lines were also transfected with RNP complexes of spCas9 and a non-targeting sgRNA (spacer = 5’- GCGUCGUCGGUCGCGAUUAA-3’). After Nucleofection, cells were grown for three days before harvesting. Knockout was confirmed by Sanger sequencing using Synthego ICE analysis tool (https: / / www.synthego.com / products / bioinformatics / crispr-analysis). Knockout pool generated for HEK293T and iPSCs had a calculated knockout score of 100% and 87%, respectively. PRINS editing in HAP1 cells PRINS editing using PEn editor (SEQ ID 30), was executed at 4 target sites: DPM2 (SEQ ID 35), PCSK9 (SEQ ID 36), PDCD1 (SEQ ID 37), TRAC (SEQ ID 38). The insertion length of the inserted nucleotides was between 8-12 bp. 4E06 cells of HAP1 WT and DCLRE1C knockout cells were seeded in 10 cm dish in IMDM media (+10% FBS, 1% pen / strep) then incubated at 37°C, 5% CO2 overnight. For transfection, cells were harvested, washed with PBS and diluted to 400,000 cells / 20 µL of Lonza SE cell line buffer. Pre-formed RNP complex of PEn protein and synthetic guides (50 picomoles) were added to 20 µL of resuspended cells. Cells were electroporated with a 4D- Nucleofector system (Lonza #: V4XC-1032) using DS-118 program. Electroporated cells were diluted in media and plated into 96-well plates. Cells were incubated at 37°C, 5% CO2 for 3 days before harvesting genomic extracts. Short amplicons of target sites were amplified by PCR with target specific primers extended with 4-bp barcodes and NGS adapters. PCR products were pooled and purified using HighPrep PCR Clean-up System (MagBio Genomics). Illumina indexes were added to the amplicons and purified again before sequencing by Next-Generation Sequencing. Analysis of targeted amplicon sequencing was performed on reads by CRISPResso2. Average insertion length at the cut site was calculated by dividing the sum of the weighted frequency of reads for each insertion size by the sum of the total amount of inserted reads (Ʃ(readsinsertion*insert length) / Ʃ(readsinsertion)) introduced by editing. The results of this experiment are shown in Figure 2A and 2B. The data shows that DCLRE1C knockout increases the average length of prime edited insertions from 6.4 to 12.2bp at the DPM2 site, from 5.8 to 9.9bp at the PCSK9 site, from 6.1 to 10.7bp at the PDCD1 site, and from 5.4 to 8.2 at the TRAC site. In other words, the Artemis knockout increases average length of prime edited insertion in HAP1 cells. PRINS editing in HEK293T cells 12,500 cells of HEK293T WT and DCLRE1C knockout were seeded in 96-well plate in DMEM media (+10% FBS, 1% Pen / strep) then incubated at 37°C, 5% CO2 overnight. For transfection, plasmids of editor (PEn) (SEQ ID 30) and springRNA (SEQ ID 31-34) were mixed at a ratio of 3:1, 100 ng total. Cells were transfected with plasmids using Fugene HD reagent, at a 6:1 ratio of reagent to plasmid. After transfection, cells were incubated at 37°C, 5% CO2 for 3 days before harvesting genomic extracts. Short amplicons of target sites were amplified by PCR with target specific primers extended with 4-bp barcodes and NGS adapters. PCR products were pooled and purified using HighPrep PCR Clean-up System (MagBio Genomics). Illumina indexes were added to the amplicons and purified again before sequencing by Next-Generation Sequencing. Analysis of targeted amplicon sequencing was performed on reads by CRISPResso2. Average insertion length at the cut site was calculated by dividing the sum of the weighted frequency of reads for each insertion size by the sum of the total amount of inserted reads (Ʃ(readsinsertion*insert length) / Ʃ(readsinsertion)) introduced by editing. The results of this experiment are shown in Figure 2A and 2B. The data shows that DCLRE1C knockout increases the average length of prime edited insertions from 6.3 to 11.5bp at the DPM2 site, from 6.4 to 10.2bp at the PCSK9 site, from 10.1 to 12.5bp at the PDCD1 site, and from 5.1 to 7.7bp at the TRAC site. In other words, the Artemis knockout increases average length of prime edited insertion in HEK293T cells. PRINS editing in human iPSC Human iPSC were cultured using DEF-CS pluripotent culturing system according to manufacturer’s instructions (Cellartis® DEF-CS™ Culture System User Manual). For transfection, cells were harvested, washed with PBS and diluted to 200,000 cells / 20 µL of Lonza SE cell line buffer. Pre-formed RNP complex of PEn protein (SEQ ID 30) and synthetic springRNA (50 picomoles) (SEQ ID 35-38) were added to 20 µL of resuspended cells. Cells were electroporated with a 4D- Nucleofector system (Lonza #: V4XC-1032) using CB-150 program. Electroporated cells were diluted in media and plated into 96-well plates. Cells were incubated at 37°C, 5% CO2 for 3 days before harvesting genomic extracts. Short amplicons of target sites were amplified by PCR with target specific primers extended with 4-bp barcodes and NGS adapters. PCR products were pooled and purified using HighPrep PCR Clean-up System (MagBio Genomics). Illumina indexes were added to the amplicons and purified again before sequencing by Next-Generation Sequencing. Analysis of targeted amplicon sequencing was performed on reads by CRISPResso2. Average insertion length at the cut site was calculated by dividing the sum of the weighted frequency of reads for each insertion size by the sum of the total amount of inserted reads (Ʃ(readsinsertion*insert length) / Ʃ(readsinsertion)) introduced by editing. The results of this experiment are shown in Figure 2A and 2B. The data shows that DCLRE1C knockout increases the average length of prime edited insertions from 6.3 to 8.4bp at the DPM2 site, from 6.8 to 8.7bp at the PCSK9 site, from 7.7 to 9.9bp at the PDCD1 site, and from 5.6 to 7.1bp at the TRAC site. In other words, the Artemis knockout increases average length of prime edited insertion in human iPSCs. Example 3 – Effect of Artemis dominant negative mutant on the average length of insertion by PRINS editing. A catalytically dead mutant of Artemis that competes for binding DNAPK with endogenous Artemis was tested for its ability to reduce Artemis activity and compare editing efficiency of PRINS editing within HEK293T cells. The mutant tested was Artemis dominant negative mutant (1-413, D37N) expressed from CMV promoter on a separate plasmid. 12,500 cells of HEK293T WT were seeded in 96-well plate in DMEM media (+10% FBS, 1% Pen / strep) then incubated at 37°C, 5% CO2 overnight. For transfection, editor plasmid (PEn) (SEQ ID 30), Artemis mutant plasmid (aPEn-2) (SEQ ID 8) and springRNA (SEQ ID 31-34) were mixed at a ratio of 3:3:1 (editor: Artemis mutant: springRNA), 150 ng total. Cells were transfected with plasmids using Fugene HD reagent, at a 6:1 ratio of reagent to plasmid. After transfection, cells were incubated at 37°C, 5% CO2 for 3 days before harvesting genomic extracts. Short amplicons of target sites were amplified by PCR with target specific primers extended with 4-bp barcodes and NGS adapters. PCR products were pooled and purified using HighPrep PCR Clean-up System (MagBio Genomics). Illumina indexes were added to the amplicons and purified again before sequencing by Next- Generation Sequencing. Analysis of targeted amplicon sequencing was performed on reads by CRISPResso2. Average insertion length at the cut site was calculated by dividing the sum of the weighted frequency of reads for each insertion size by the sum of the total amount of inserted reads (Ʃ(readsinsertion*insert length) / Ʃ(readsinsertion)) introduced by editing. The results of this experiment are shown in Figure 3A and 3B. The data shows that DCLRE1C knockout increases the average length of prime edited insertions from 6.2 to 7.0bp at the DPM2 site, from 6.2 to 6.9bp at the PCSK9 site, from 10.2 to 10.3bp at the PDCD1 site, and from 4.9 to 5.2bp at the TRAC site. In other words, the expression of Artemis dominant negative mutant (D37N 1-413, aPEn-2) increases average length of prime edited insertion. Example 4 – Effect of DCLRE1C (Artemis) mRNA knockdown by siRNA on the average length of insertion by PRINS editing. Editing efficiency of PRINS editing within HEK293T cells in the absence of Artemis was tested by using siRNA pool (L-004269-00-0010, Dharmacon) targeting DCLRE1C mRNA to knockdown expression of DCLRE1C and compare editing efficiency. 750,000 HEK293T WT cells were seeded in a 6-well plate in DMEM media (+10% FBS, 1% Pen / strep) then incubated at 37°C, 5% CO2 overnight. The next day, cells were transfected with 90 picomoles siRNAs (non-targeting control, DCLRE1C targeting) using RNAiMAX reagent. After transfection, cells were incubated at 37°C, 5% CO2 for 2 days. After the second day, cells were harvested and re-seeded in a 96-well plate at 25,000 cells per well then incubated at 37°C, 5% CO2 overnight. The following day, cells were transfected with 1 picomole of siRNAs and 200 ng plasmids (3:1, editor: guide RNA) (SEQ ID 30 and 31). After transfection, cells were incubated at 37°C, 5% CO2 for 3 days before harvesting genomic extracts. Short amplicons of target sites were amplified by PCR with target specific primers extended with 4-bp barcodes and NGS adapters. PCR products were pooled and purified using HighPrep PCR Clean-up System (MagBio Genomics). Illumina indexes were added to the amplicons and purified again before sequencing by Next- Generation Sequencing. Analysis of targeted amplicon sequencing was performed on reads by CRISPResso2. Average insertion length at the cut site was calculated by dividing the sum of the weighted frequency of reads for each insertion size by the sum of the total amount of inserted reads (Ʃ(readsinsertion*insert length) / Ʃ(readsinsertion)) introduced by editing. The results of this experiment are shown in Figure 4A and 4B. The data shows that DCLRE1C knockdown increases the average length of prime edited insertions from 5.7 to 7.1bp at the DPM2 site. In other words, the DCLRE1C siRNA knockdown increases the average length of prime edited insertion. Example 5 – Effect of the combination of Artemis knockout and PRINS to integrate Bxb1 attB sites. DCLRE1C knockout cell lines was used in HEK293T to compare the integration of large (38bp) insertion of the attB sequence of Bxb1 serine integrase into different target sites (AAVS1 (PPP1R12C), LDLR, CFTR). The protocol for HEK293T transfection was the same as in previous experiments (SEQ ID 30, 39-44). Short amplicons of target sites were amplified by PCR with target specific primers extended with 4-bp barcodes and NGS adapters. PCR products were pooled and purified using HighPrep PCR Clean-up System (MagBio Genomics). Illumina indexes were added to the amplicons and purified again before sequencing by Next-Generation Sequencing. Analysis of targeted amplicon sequencing was performed on reads by CRISPResso2. Figure 5A shows that DCLRE1C knockout increases integration of the attB sequence (38bp) at the AAVS1 site from 41.3 to 50.7%, when inserted on the negative strand, and from 30.8 to 38.1%, when inserted on the positive strand. Figure 5B shows that DCLRE1C knockout increases integration of the attB sequence (38bp) at the LDLR site from 23.5 to 30.1%, when using spacer 2, and from 18.7 to 24.9%, when using spacer 4. Figure 5C shows that DCLRE1C knockout increases integration of the attB sequence (38bp) at the CFTR site from 11.2 to 18.4%, when using spacer 3, and from 20.2 to 28.2%, when using spacer 6. In other words, Artemis knockout increases integration efficiency of large insert (attB) with PRINS editing. Example 6 – Effect of abasic site modification on the precision of PRINS editing. Chemically modified springRNA with an abasic site in between the sgRNA scaffold and the RT template (spaceRNA) was used to compare editing efficiency with a regular springRNA of PRINS at the DPM2 site in both wildtype and DCLRE1C knockout HEK293T cells. 12,500 cells of HEK293T WT were seeded in 96-well plate in DMEM media (+10% FBS, 1% Pen / strep) then incubated at 37°C, 5% CO2 overnight. The next day, cells were transfected with 100ng of editor plasmid (PEn) (SEQ ID 30) using Fugene HD reagent, at a 6:1 ratio of reagent to plasmid, then transfected the next day with 2 pmols of synthetic springRNA or spaceRNA using Lipofectamine RNAiMAX reagent (SEQ ID 35, 174). After the second transfection, cells were incubated at 37°C, 5% CO2 for 2 days before harvesting genomic extracts. Short amplicons of target sites were amplified by PCR with target specific primers extended with 4-bp barcodes and NGS adapters. PCR products were pooled and purified using HighPrep PCR Clean-up System (MagBio Genomics). Illumina indexes were added to the amplicons and purified again before sequencing by Next- Generation Sequencing. Analysis of targeted amplicon sequencing was performed on reads by CRISPResso2. Figure 6 shows that the spaceRNA reduces the amount of scaffold incorporated reads after PRINS editing compared with the springRNA. This leads to more precise editing in both WT and DCLRE1C knockout cells. In other words, chemically modified springRNA with abasic site to block reverse transcription of the pegRNA extension into the sgRNA scaffold improves the precision of PRINS editing. Example 7 – Effect of the combination of Artemis knockout and PRINS to integrate epitope tags. DCLRE1C knockout cell lines was used in HEK293T to compare the integration of large (30bp) insertion of the FLAG tag sequence into different target sites (DNMT1, HEK3, RNF2, RUNX1, VEGFA). The protocol for HEK293T transfection was the same as in previous experiments (SEQ 30, 45-49). Short amplicons of target sites were amplified by PCR with target specific primers extended with 4-bp barcodes and NGS adapters. PCR products were pooled and purified using HighPrep PCR Clean-up System (MagBio Genomics). Illumina indexes were added to the amplicons and purified again before sequencing by Next-Generation Sequencing. Analysis of targeted amplicon sequencing was performed on reads by CRISPResso2. Figure 7 shows that DCLRE1C knockout increases integration of the FLAG sequence (30bp) at the DNMT1 site from 13.8 to 17.7%, at the HEK3 site from 5.7 to 8%, at the RNF2 site from 13.6 to 19%, at the RUNX1 site from 13.9 to 18.3%, and the VEGFA site from 6.8 to 8.5%. In other words, Artemis knockout increases integration efficiency of large insert (FLAG) with PRINS editing. Example 8 – Screen to discover antisense oligonucleotides that can downregulate expression of DCLRE1C (Artemis) in human cells. ASOs were designed to target the DCLRE1C gene in human cells. Synthesized ASOs were transfected in HEK293T cells to determine knockdown efficiency compared to non- targeting ASO. 100,000 cells of HEK293T WT were reverse transfected with each of the targeting (SEQ ID 57-118) or non-targeting ASOs (SEQ ID 178) (30pmols) using Lipofectamine RNAiMAX reagent into a 24-well plates in DMEM media (+10% FBS, 1% Pen / strep), then incubated at 37°C, 5% CO2 for 3 days before extracting the RNA (Qiagen RNeasy spin kit). 1000ng of RNA was reverse transcribed into cDNA using High-capacity reverse transcriptase kit (Applied Biosystems). Then, Ct values was determined by qPCR using Taqman fast advanced master mix (Thermo) with 4uL of cDNA reaction and Taqman assay kits for DCLRE1C (Hs01052788_m1, Thermo) or TBP (4332659, Applied Biosystems) as a reference gene. qPCR data was analyzed by delta delta Ct method using the Ct value of the non-targeting ASO as the control value. Figure 8 shows that three ASOs, marked with darker font on the graph, achieved over 90% knockdown efficiency in HEK293T cells. Example 9 – Screen to discover antisense oligonucleotides that can downregulate expression of Dclre1c (Artemis) in mouse cells. ASOs were designed to target the Dclre1c gene in mouse cells. Synthesized ASOs were transfected in AML-12 cells to determine knockdown efficiency compared to non-targeting ASO. 100,000 cells of AML-12 WT were reverse transfected with each of the targeting (SEQ ID 119-173) or non-targeting ASOs (15pmols) (SEQ ID 178) using Lipofectamine RNAiMAX reagent into a 24-well plates in DMEM media (+10% FBS, 1% Pen / strep), then incubated at 37°C, 5% CO2 for 3 days before extracting the RNA (Qiagen RNeasy spin kit). 1000ng of RNA was reverse transcribed into cDNA using High-capacity reverse transcriptase kit (Applied Biosystems). Then, Ct values were determined by qPCR using Taqman fast advanced master mix (Thermo) with 4uL of cDNA reaction and Taqman assay kits for DCLRE1C (Mm00455364_m1, Thermo) or ACTB (4352933E, Applied Biosystems) as a reference gene. qPCR data was analyzed by delta delta Ct method using the Ct value of the non-targeting ASO as the control value. Figure 9 shows that five ASOs, marked with darker font on the graph, achieved over 80% knockdown efficiency in AML-12 cells. Example 10 – Comparisons of different gene knockdown modalities (CRISPRi, siRNA, and ASOs) on the knockdown efficiency of DCLRE1C (Artemis) in HEK293T cells. The top three ASOs targeting DCLRE1C tested in Example 8 was directly compared with commercially available siRNA pool ((L-004269-00-0010, Dharmacon), and CRISPRi method. CRISPRi technique was accomplished using mRNA expressing dCas9 fused with KRAB domain and demethylase domains and a sgRNA targeting the CpG island in the DCLRE1C promoter. 100,000 cells of HEK293T WT were reverse transfected with 1) CRISPRi mRNA (100ng) (SEQ ID 175) and either targeting (SEQ ID 176) or non-targeting sgRNA (SEQ ID 179) (2pmols) with Lipofectamine MessengerMax reagent, 2) 15pmols of either targeting ((L- 004269-00-0010, Dharmacon) or non-targeting siRNA (Dharmacon) with Lipofectamine RNAiMAX reagent, or 3) 15pmols of either targeting (SEQ ID 57, 84, 116) or non-targeting ASOs (SEQ ID 178) with Lipofectamine RNAiMAX reagent into a 24-well plates in DMEM media (+10% FBS, 1% Pen / strep) in biological triplicates, then incubated at 37°C, 5% CO2 for 1,2,3, or seven days before extracting the RNA (Qiagen RNeasy spin kit). 1000ng of RNA was reverse transcribed into cDNA using High capacity reverse transcriptase kit (Applied Biosystems). Then, Ct values was determined by qPCR using Taqman fast advanced master mix (Thermo) with 4uL of cDNA reaction and Taqman assay kits for DCLRE1C ((Hs01052788_m1, Thermo) or TBP (4332659, Applied Biosystems) as a reference gene. qPCR data was analyzed by delta delta Ct method using the Ct value of the non-targeting ASO as the control value. Figure 10 shows that CRISPRi repression led to over 90% knockdown efficiency for up to seven days. ASOs knockdown led to over 90% knockdown efficiency for up to three days before recovering. Example 11 – Comparisons of the effect of CRISPRi repression of DCLRE1C (Artemis) on PRINS editing in different cells lines. CRISPRi technique was accomplished using mRNA expressing dCas9 fused with KRAB domain and demethylase domains and a sgRNA targeting the CpG island in the DCLRE1C promoter) (SEQ ID 175). 500,000 cells of HEK293T, HeLa, and HepG2 were forward transfected with CRISPRi mRNA (100ng) (SEQ ID 175) and either targeting (SEQ ID 176) or non-targeting sgRNA (SEQ ID 179) (2pmols) with Lipofectamine MessengerMax reagent into a 6-well plates in appropriate growth media in biological triplicates, then incubated at 37°C, 5% CO2 for five days to achieve desired knockdown. Separately, 200,000 K562 cells were electroporated with a 4D- Nucleofector system (Lonza #: V4XC-1032) using FF-120 program using 2000ng of CRISPRi mRNA (SEQ ID 175) and 100pmols of either targeting (SEQ ID 176) or non-targeting sgRNA (SEQ ID 179) in biological triplicates, then seeded into a 6-well plate into appropriate growth media and incubated at 37°C, 5% CO2 for five days to achieve desired knockdown. After five days, all the cells were harvested and electroporated with a 4D- Nucleofector system (Lonza #: V4XC-1032) with 2000ng of PEnMAX mRNA (SEQ ID 30) and 200pmols of synthetic springRNA to insert into AAVS1 (PPP1R12C) (SEQ ID 177), DPM2 (SEQ ID 35), and PCSK9 (SEQ ID 36) genomic sites using CM-130 (HEK293T), CN-114 (HeLa), EH-100 (HepG2), or FF-120 (K562) program on the Lonza electroporator. After electroporation, cells were seeded into a 96 well plate and incubated at 37°C, 5% CO2 for three days before harvesting genomic extracts. Short amplicons of target sites were amplified by PCR with target specific primers extended with 4-bp barcodes and NGS adapters. PCR products were pooled and purified using HighPrep PCR Clean-up System (MagBio Genomics). Illumina indexes were added to the amplicons,and purified again before sequencing by Next-Generation Sequencing. Analysis of targeted amplicon sequencing was performed on reads by CRISPResso2. For plotting, % reads with precise or intended insertion and reads with additional sgRNA scaffold integration are compared between each cell line, target site, and CRISPRi targeting sgRNA. Figure 11 shows that CRISPRi knockdown with DCLRE1C targeting sgRNA increases the amount of intended or longer insertions at all three target sites and in all four cell lines. Example 12 –The effect of ASOs knockdown of DCLRE1C (Artemis) on PRINS editing in HEK293T cells. 800,000 cells of HEK293T were reverse transfected with non-targeting (SEQ ID 178) or targeting ASOs (35pmol) (SEQ ID 57) with Lipofectamine RNAiMAX reagent into a 6- well plates in appropriate growth media in biological triplicates, then incubated at 37°C, 5% CO2 for three days to achieve desired knockdown. After three days, all the cells were harvested and electroporated with a 4D- Nucleofector system (Lonza #: V4XC-1032) with 2000ng of PEnMAX mRNA (SEQ ID 30) and 200pmols of synthetic springRNA to insert into AAVS1 (PPP1R12C) (SEQ ID 177), DPM2 (SEQ ID 35), and PCSK9 (SEQ ID 36) genomic sites using CM-130 program on the Lonza electroporator. After electroporation, cells were seeded into a 96 well plate and incubated at 37°C, 5% CO2 for three days before harvesting genomic extracts. Short amplicons of target sites were amplified by PCR with target specific primers extended with 4-bp barcodes and NGS adapters. PCR products were pooled and purified using HighPrep PCR Clean-up System (MagBio Genomics). Illumina indexes were added to the amplicons,and purified again before sequencing by Next- Generation Sequencing. Analysis of targeted amplicon sequencing was performed on reads by CRISPResso2. For plotting, % reads with precise or intended insertion and reads with additional sgRNA scaffold integration are compared between each target site and between types of ASOs. Figure 12 shows that ASOs knockdown of DCLRE1C increases the amount of intended or longer insertions at all three target sites in HEK293T cells. Example 13 –The effect of ASOs knockdown of DCLRE1C (Artemis) on PRINS- mediated protein tagging of MIF1 gene in HEK293T cells. 800,000 cells of HEK293T were reverse transfected with non-targeting (SEQ ID 178) or targeting (SEQ ID 57) ASOs (35pmol) with Lipofectamine RNAiMAX reagent into a 6- well plates in appropriate growth media in biological triplicates, then incubated at 37°C, 5% CO2 for three days to achieve desired knockdown. After three days, all the cells were harvested and electroporated with a 4D- Nucleofector system (Lonza #: V4XC-1032) with 2000ng of PEnMAX mRNA (SEQ ID 30) and 200pmols of synthetic springRNA to insert four different epitope tags (poly-histidine tag, FLAG tag, Myc-tag, and HIBIT tag) (SEQ ID 50-53) onto the C-terminal end of the MIF1 protein genomic site using CM-130 program on the Lonza electroporator. After electroporation, cells were seeded into two 96-well plates and four 6-well plate and incubated at 37°C, 5% CO2 for three days to collect genomic DNA and to conduct a HIBIT lytic assay test (96-well plates), or seven or more days to collect protein for Western blot. For sequencing, short amplicons of target sites were amplified by PCR with target specific primers extended with 4-bp barcodes and NGS adapters. PCR products were pooled and purified using HighPrep PCR Clean-up System (MagBio Genomics). Illumina indexes were added to the amplicons, and purified again before sequencing by Next-Generation Sequencing. Analysis of targeted amplicon sequencing was performed on reads by CRISPResso2. For plotting, % reads with precise intended insertion are compared for each protein tag and between types of ASOs. Nano-Glo® HiBiT Lytic Detection System (Promega) was used to measure activity of the HIBIT tagged MIF1 protein in cell lysates. Briefly, cell culture media was removed from 96-well plate and 100uL of PBS + 100uL of HIBIT lytic buffer with LgBit (1 / 2000) and Nano-glo substrate (1 / 1000) was added to the cell and mixed by pipetting. Cells were incubated for 10min then Relative luminescence units (RLUs) was measured using a plate reader (Pherastar). For Western blot, protein were extracted from the cells (1E06 cells) with RIPA buffer and protease inhibitors (Thermo). Protein lysates were sonicated for 30sec at 50% intensity. Protein amount were measured with Pierce BSA protein assay kit (Thermo). Proteins were diluted in LPS loading buffer and DTT (Thermo) at 1ug / uL.30ug of protein was separated by electrophoresis with a 12% NuPAGE gel (Thermo). Protein was then transferred to a nitrocellulose membrane with the iBlot2 transfer system (Thermo). Membranes were blocked with 5% milk in TBS-T for 30min, then incubated with a 1 / 1000 dilution of the appropriate primary antibodies (rabbit anti- HIStag, Myc-tag, FLAG-tag (Cell Signalling) and rabbit anti-HIBIT tag (Promega)) overnight at 4deg Celsius in 5% milk in TBS-T. After three washes in TBS-T, membranes were incubated for 1h with HRP-conjugated anti- Rabbit secondary (1 / 2000 dilution, Thermo) diluted in 5% milk in TBS-T. After washing three times with TBS-T, membranes were exposed to SuperSignal™ West Pico PLUS Chemiluminescent Substrate (Thermo) and pictured with chemiluminescent imager (Biorad). Figure 13 shows that ASOs knockdown of DCLRE1C can improve the integration of different protein tags in frame with the MIF1 gene in HEK293T cells. Example 14 –The effect of ASOs knockdown of DCLRE1C (Artemis) on PRINS- mediated insertion of attB site and loxP site at therapeutically relevant sites in human cell lines. 1,500,000 cells of HepG2 LDLR knockout cell or 800,000 cells of HEK293T were reverse transfected with non-targeting (SEQ ID 178) or targeting (SEQ ID 57) ASOs (35pmol) with Lipofectamine RNAiMAX reagent into a 6-well plates in appropriate growth media in biological triplicates, then incubated at 37°C, 5% CO2 for three days to achieve desired knockdown. After three days, all the cells were harvested and electroporated with a 4D- Nucleofector system (Lonza #: V4XC-1032) with 2000ng of PEnMAX mRNA (SE ID 30) and 200pmols of synthetic springRNA to insert the 38bp attb site of the Bxb1 serine integrase into the first intron of the LDLR locus (SEQ ID 54) within the HepG2 LDLR knockout cell model or synthetic springRNA to insert the 34bp loxP or lox71 site of the Cre recombinase genomic sites into the DMD gene (SEQ ID 55-56) upstream of exon 45 within HEK293T cells using EH-100 (HepG2) or CM-130 (HEK293T) program on the Lonza electroporator. After electroporation, cells were seeded into a 96 well plate and incubated at 37°C, 5% CO2 for three days before harvesting genomic extracts. Short amplicons of target sites were amplified by PCR with target specific primers extended with 4-bp barcodes and NGS adapters. PCR products were pooled and purified using HighPrep PCR Clean-up System (MagBio Genomics). Illumina indexes were added to the amplicons,and purified again before sequencing by Next-Generation Sequencing. Analysis of targeted amplicon sequencing was performed on reads by CRISPResso2. For plotting, % reads with precise or intended insertion and reads with additional sgRNA scaffold integration are compared between each target site and between types of ASOs. Figure 14 shows that ASOs knockdown of DCLRE1C increases the amount of intended or longer insertion of the attB sequence or loxP / lox71 sequence into their respective target sites. Example 15 –The effect of ASOs knockdown of DCLRE1C (Artemis) on PRINS- mediated protein tagging of ACTB gene in K562 cells. 300,000 cells of K562 were electroporated with non-targeting (SEQ ID 178) or targeting (SEQ ID 57) ASOs (100pmol) using FF-120 program on the Lonza electroporator (4D- Nucleofector system (Lonza #: V4XC-1032) and seeded into a 6-well plates in appropriate growth media in biological triplicates, then incubated at 37°C, 5% CO2 for three days to achieve desired knockdown. After three days, all the cells were harvested and electroporated with the Nucleofector again with 2000ng of PEnMAX mRNA (SEQ ID 30) and 200pmols of synthetic springRNA to insert four different epitope tags (poly-histidine tag, FLAG tag, Myc-tag, and HIBIT tag) onto the C-terminal end of the ACTB protein genomic site (SEQ ID 180-183) using FF-120 program on the Lonza electroporator. After electroporation, cells were seeded into two 96-well plates and four 6-well plate and incubated at 37°C, 5% CO2 for three days to collect genomic DNA and to conduct a HIBIT lytic assay test (96-well plates), or seven or more days to collect protein for Western blot. For sequencing, short amplicons of target sites were amplified by PCR with target specific primers extended with 4-bp barcodes and NGS adapters. PCR products were pooled and purified using HighPrep PCR Clean-up System (MagBio Genomics). Illumina indexes were added to the amplicons, and purified again before sequencing by Next-Generation Sequencing. Analysis of targeted amplicon sequencing was performed on reads by CRISPResso2. For plotting, % reads with precise intended insertion are compared for each protein tag and between types of ASOs. Nano-Glo® HiBiT Lytic Detection System (Promega) was used to measure activity of the HIBIT tagged MIF1 protein in cell lysates. Briefly, cell culture media was removed from 96-well plate and 100uL of PBS + 100uL of HIBIT lytic buffer with LgBit (1 / 2000) and Nano-glo substrate (1 / 1000) was added to the cell and mixed by pipetting. Cells were incubated for 10min then Relative luminescence units (RLUs) was measured using a plate reader (Pherastar). For Western blot, protein were extracted from the cells (1E06 cells) with RIPA buffer and protease inhibitors (Thermo). Protein lysates were sonicated for 30sec at 50% intensity. Protein amount were measured with Pierce BSA protein assay kit (Thermo). Proteins were diluted in LPS loading buffer and DTT (Thermo) at 1ug / uL.30ug of protein was separated by electrophoresis with a 12% NuPAGE gel (Thermo). Protein was then transferred to a nitrocellulose membrane with the iBlot2 transfer system (Thermo). Membranes were blocked with 5% milk in TBS-T for 30min, then incubated with a 1 / 1000 dilution of the appropriate primary antibodies (rabbit anti- HIStag, Myc-tag, FLAG-tag (Cell Signalling) and rabbit anti-HIBIT tag (Promega)) overnight at 4deg Celsius in 5% milk in TBS-T. After three washes in TBS-T, membranes were incubated for 1h with HRP-conjugated anti- Rabbit secondary (1 / 2000 dilution, Thermo) diluted in 5% milk in TBS-T. After washing three times with TBS-T, membranes were exposed to SuperSignal™ West Pico PLUS Chemiluminescent Substrate (Thermo) and pictured with chemiluminescent imager (Biorad). Figure 15 shows that ASOs knockdown of DCLRE1C can improve the integration of different protein tags in frame with the ACTB gene in K562 cells.

[0002] Seq A (Full gene sequence), B (CDS), C (codon optimised CDS), D ID (Amino Acid Sequence), E (DNA sequence), F (RNA sequence) Human gene DCLRE1C encoding Artemis 1 A CGGAACGAAGAATGATTTCTAAGCGCAGTTCCGCAGCCCACTCACCTCGTCGGCTGGGGCCACC TGCTCTGGGAGTTTCGATTTCCCTTCCCGCGACTGCACCTCCACAGACATGGGCAACGCCTTAC CAGAGCAACACCTGTGTTTGTTGGGCGGGAATGAGCCTTGCACTGGGCAGGGCTCAGGGCCCAT CGCGTGCAGCGAAGCGCGGGTGATTTAAACCCAAGCAGCGGGCGCCTAGAACCCGACCGGATGC TCCTTGACTTTGCCCCCGGTCTCCGGACTCCTCTGATTGGACGTGGCTGCGTTCGGCCGCCCAA TGGCGAGGCAGCGCGCGGCTTCCCGGAAGTGGCGGCGCGGTCAGGGCTGGCCTTGGCTTCAGCT GCGGTTTTGGGGTCCCGGACTCTGGGATCGGCGGCGCTATGAGTTCTTTCGAGGGGCAGATGGC CGAGTATCCAACTATCTCCATAGACCGCTTCGATAGGGAGAACCTGAGGGCCCGCGCCTACTTC CTGTCCCACTGCCACAAAGGTGAGTGAGGGCTGCGCGTCGCCCGCTCCCGGGGCGCTGGGGGCT GGAGAGAGGACAGGAGGGGGCCGGCCCTGGAGCAAGGAGCTGCAGCCTGTGGGAAGCCAGCGAG GGGGCGGCCAGCACACGCCTTGTCCCAGTCGGGCTCTTCAGCCTCTCAAAGGCTTCATCTATTT TCGGATGTGGTCAACGCGGCGTAACGGCGCCTGCCAGTTGCGCCCCGGGCCGGCTTGGTCAAGC ACTGCTAGTAGTTTCTCTTGGTAGCTTTGCTGGTGGCCGATGATCAGAGATTGGCGAGGGTTAG TACTTCCCTCAGAGCCTCGCTACCATGTATGAAGAAAACAAGTTTCAGATCCATTTGACCACAC CCTCAAACATTGGTCAGCAAGCAGGAGACTCAGACACACACACAACTGTGGAACAGCCCGCCTA AGAGCTCCACGAAGTGCAAGCTCCTTGGCCTTTGGGTGTTCTGTCCGTATCCAATATGAAAGTT TCGTTCTAGTTTAGGTTGGAGGGATGTTTCCCTTCTAGATGGTATCAGGCAACCTGAAAAGCTA CTATGATTTCACAGCTGGATCCTTTCACAGCTGGGCCGATTTAGGGATTAAGGTTAGAGTGTCG CTGATGCTCCAAGCAGAGATTGGAGCTAAGTTCCAGAGTTTAAATACCGCTAACTTGACAACCA TTGTTCATTTTCACTTCTATTGTGCTAACAAGTCACTAACTTTTACCAGGGAAAACAGTTTTAA TGCTCATTGTGCTAATTCGCCCAGCCATTAGTGTTAATTGGAGAAAATGATAAACGGAATCACT GGAGTTGCTGCCTCCTGCTGTGTGGCCTTGCAGCGTGCTGGAGCAGGAAGCTCCCACTACCCTG TGGAGTCAATCAGCGTAACAAACCTATCTGTACCTGCGCAGTAGGAAAGTATTTTAAAGTAAAT TACAGGTATCCAAACACAGCCTTTCCTCACAGGGTTGGTGTGAAGGCCAGCTATGTTGTTTTGT GTGTGGAATCAATCACTTGGACTATAAATCGTTGAAGTTACTGCTTCTGCGAAATGTCTCTGCT TTTTTTTTCCACAAAGCCACCAGTGATTTCTCTTTAATGGGAAAATCTGGACCTCTTCTCGTGC GTTGCCGTATTCGCATCGTGCACGTCTTTGAGCATCTCCTTCTTCTTTTTCTTTTTTTTGGAGA CAGGGTCTCCCTTTGTCGCCCAGGCTGGAGTACAGTGTGGCACATGCTCTCTGCTCAAGTAGTT GGGACTACAGGAGTCAGCCACCATGCCTAGCTAATGTTTGTATTTTTATTATTATTTTGAGGTG GAGTCTCCATCACCAGGCTGGAGTGCAGTGGCGTGATCTCTGTTCACTGCAACCTCCGCCTCCT GGGTTCAAGCGATTCTCGTGCCTCAGCCTCCCAAGTAGCTGGAGTTACAGGCACGCACCACCAC ACCCAGGTAATTTTTGTGTTTTTAGTAGAGATGATGTTTCACCATGTTGGCCAGGCTGGTCTCG AACTCCTGGCCTCAGGTAGATCCACCCACCTCAGCCTCCCAAAGTGTTAGGATTACAGGTGTGA GCCGCTGTGCCTGACACATTTCTGGTTTTGTTTTTCATTGAGAATCCACTGCTGGACGAGGATA TGCCTATTTTTACTTTTTGTGTAGAGCCGCACTGGAGTCTCTGAACTCAAAATGGGCTAGCCAG GATTAAAGTATACTTCCGAAACTTGCACTTCGTGTTTAGGATGGCTGAGTTTGGAGAAATAATA AATCTAAAGGAATTTGAAATCATCATAAGTTTGTGCATTAAGCCAGAAATGGACTCTTCCCTAC TGTTGAACAGTCTATAACAACTTTTTCTGTTCTCTGACCACATGTGGATCTGCTTAGTCAACCA GGACATAAACTCATCAAGGGTGAAAACACAACTTCTGCTTTTGGAGGTTTCTCACATTGCCTTC TGTTGGCTTTTCACCTTTTTGGGACACAGGCTTCTTTGATTATGATATGGACTATCTCCACAAA ATTCATATGTTGAAGCCCTAACCCCCAAAGCGACTGTATTTGGGGCTGGGGCTTTTAGGAGGAA AATAAGTTTAAGTGGGGTCCTACCGTGGTGTCCTACTCTGATAGGATTAGTTTCCTTACAAGAG AAGGAAGAGAGAGGGCGCTCTGTCCTCATGCGGGGCCTAGGAAAGCCATGTGAGTGCATAGTGA GAAGGCGGCTGTCTGTAAGTTAGGAAAAGTGCCCTCTCCAGAAACCAAATCGCCCCGCATCTTG ATCTTCCCAGCTTCCTGAACTGTGAGAAATACCTTTTTGGTGTTGAAGGCAACCAAAACACTAC CTTTCCTTACAGCGCTGGTGTGAAGGCCAACTATGGTATCTATGGTATCTTGTGATAGCAGCTC AAACATGAGAAACTGTATGGACTCTTTTGCTAGAAAAAATGCATGGAAACCCATCCACATCACT TCCTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTGAGACAGGGTTTTGCTCTGTCACCCAGGC TGGAGTGCAGTGGTGCGATCTCGGCTCACTGCAGCCTTCACCTCCTGGACTCAACCAATCCTCC CACCTCAGCAAGTACTCCCACCTGAGTAGTTGGGATTACAGACATGCACCATCATGCCTGGCTA ATTTTTCTATTTTTTATAGAGAGACAGGATTTCCCCATGTTGCCCAGGCTGGTATCGAACTCCT GGGTGCAGGTGATCCACTCACCTCAGCCTCCCAAAGTGCTGGGATGACAGGTGTGAGCTACCAC ACCCAGCCCCACATCACATTTTGATATAATTCGGAGTAGGCTATGGACCCACCTGATGCTTATT TGTGGGCCATCTGGAAGCCAATGCTGTGTGCAGGGTGGGCTTTACTAAGCATCATCAGTAAGTT CTGAAAGATGAGAGGGCCCCCCGACCCCTGAGACCTGAGATAGTGGCCCAGGGTTGGGGAAATC CCCTAGAGGGGACAATTTATGATGGTTGCCAAGGAAAAGGAAAACCTCCCTGGAAAAGCAGACC TGGGTGCAGTTCCAGCCACACAAAGCAAACCCATCCAGTTCTTGTGACTACCAGCTGGAAGGGG CCTCAGGGTGGTGAGGATGGGGGACCATGATGCACCATGCAGGGTGCTGCCTGCTTAGTCAGTG TGGGAGCAGGATGCAGAGTCTGCATTCAGCCTCCTCTTTGCCATGGCGCAAACTCTTTGGAAAC TCCAATTACGGAGAATGCTGCCCAGGGATATACCCATAGGCCCTAAAAGACTGGACCAGATATC CCTTGAGGGAATTTACCCAGTGGGAGACAGGTGGACTCTCCTGGAGGCATATATACAATCAAGG GCTGCCAAGTGACATGTGGTGACTGCTCTGCTTTCACTGGGTCTAATGATGGCCACACGACATA TAAATTGAGGGGGTGCTTGTGTGTGTGTGTGGTGGTGCTCGTGGTAATTAGAATTGGTTTGGTT TAGCTAAGCAATTTATTGTTCTTGTTTTTTTTTTTTTTTTTTTGGTTATTATTTATTTTTGAGA TGGAGTTTCACTCTAGTTGCCCAGGCTGGAGTGCAATGGTACAATCTCAGCTCACCGCAACCTC TGCCTTCGGGGTTCAAGCAATTCTCCTATCTCAGCCTCCCAAGTAGCTGGGATTACAGCCATGC GCCACCAGCCCCAGCTAATTTTATATTTTTAGTGGAGACAGGGTATCTCCGTATTGGTCAGGCT GGTCTCGAACTCCCAACCTCAGGTGATCCGCCTGCCTCGGCCTCCCAAAGTGCTGGGGTTACAG GCATGAGCCACCGCGCCCAGCCGTTTGTTTGTTTTTGAGATGAAGTCTCACTCTGTCGCCCAGG CCGAAGTGCAGTGTTATGGCCTTGGCTCACTGCAACCTCTACCTCCCATGTTCAAGTGATTGTC CTGCCTCAGCCACCCGAGTAGCTGGGATTATAGGGGTGTGCTACTATTCATGGCTAATTTTTGT ATTTTTAGTAGAGATGGGGTTTTACCATGTTGGCAAGGTTGGTCTTGAACTTCTGACCTCAGGT GATCCGCCTACGTCGGCCTCCCAAAGTGTTGGGATTACAGGCAAGAGCCACCATGTCCAACTGG TTTAGTTAAACAATTTAGAGCTGTTTGATCATTGTTGTCTGGGCCTTTACTTGCTAAAGATTCA GAATATATTGGAATGCATGATATACTTAATGTAATAGTCGGTCTAATTGCTACCTTTCTGTTGT CTGTGTCTGTTAATGTGGAGCGCTGTGGAGCAAGTCTTTGTGGATAGTAATATTCCCCTTTCAA TCCATCACAGTAGGCTGAGAAGATGACGAAACACTTACTCTGAACCTGAGTGATTTCCCAGCAG ACTCCATGACCACGAACTTGAATTTCTAGATAGACTGATTTAAGTGGCAGAAAGTGAATGGGTC CCATAGAGCTTGGCTCGAAGGATGGTTGGATTGAAATGAAGTAAGAGTGGAGGGCTAGAAGCAG TTCTCATTCTTCTGTGGCTGCCCAGAGTGATTTAAACTCTGGCCTATGATGCACAGAATCACTC TCCTTTTAAATTGACTTGGATGGCTCAGAAATGGGCAGCCGGTCCTGTTCTGAGGAGGATTCTT CACTTGCAGAAGAAAGAGCTCATAGCCCATGTGAATCAATTCTTATAAAAGCAAACCTCATGGG TTTTCTCTTGAAGCTGAAAAAGAAGACGACTGTTTCCCTTGGGCTAAGGAATCCTCTGGAAAAA CATATTCATGAGTTTTTGTTCTTTTGTTTTTAGATCACATGAAAGGATTAAGAGCCCCTACCTT GAAAAGAAGGTTGGAGTGCAGGTAATTTATTTTGCTACTTGTGTTTTTAAGCAAACATTTTAAT TGAGAGATAACAACTGTACAGAAAAGTATATACATCCAAGCATATAGTCATTTACAAAATGAAC GCATCACCCAGATTAAGAAATAGGACAGTACCAATATCCCAGACCCCTCTTACCTCCCAACTCA TTCCCTCCTCCCAAAGGTAACCTCTATTCTGACTTTTGTCATCATGGGTTAGCTTTGGCTGTTT GTGAACTTGATATATATATATATATATATAATCCTACCAAATACACTCTCTAAAAACAACAACA ACAACAACGACAGCAACAAAAAAAACAGAGATGGAGTTTTGCTATGTCGCCCAGGCTGATCTCG AACTCCTGGCCTCAGGTGATCCTCCTGCCTCATTCTTCCAAAGGGCTGGCATTATAGATGTGAG CCACTGGCACCTGGCCCCAAATATACCCTTTTATATTTGTTTTACTTTACTTAACTTTGTATTT GTGTGATTTATCTATGCTGCTAGGTACAGCAGTAACTCACTCCATGTTATTTCTGTAAGAGTAT ATGAGAGAGAATGGCTGTTCCATTGTAAAGGATCATATAATACTGGATTTTTTCTTAAAGCTGA ACTGTTAGATGCTTCTCTTGCAGCCATTGCCTACATCTAAATTCCCCCTTCTCAAGATACATAT TTGAAAAGGGCCAGTGGATGTCAGGCTTCTCTGCTAATTGATAGCAATACTCTGTCTTCTTGAT AATGATAGCTAACGTTTATTGAATACTTACTGTATCTTGGCACTGTGTATTTTTTGTTCAACAA TTTTTTTTTTTTTTGTAGAGACGGGGACTTACCATGTTGCCCAGGCTGGTTGTAAACTCCTGGC TTCAAGTGATCTCCCATCTTGGCCTCCCAAAGCCCTGGGCTTATAGGCATGAGCCTTTGCACCT GGCCAATAATTTTTTATTACTTTATTTGTATTTACTTATTGACTTTTGTGACAGGGTGTTGCTC TGTCGCCCAGGCTGGAGTGCAGTGGCACGATCTCAGCTCACTGCAACTTCTTTTCGAGTGATTC TTTTGCCTCAGCCACCGGAGTAGCTGGGATTACAGGCACCCACCACCACGCCCAGCTACTTTTT GTATTTTCGGTAGAGAGGGGTTTTACCATGTTCGCCAGGCTGGTCTCGAACTCCTGACCTCAAG TGATCTGCCTGCCTCAGCCTCCCAAAGTGTTGGGATTACAGGCATGAGCCACCACTCCTGGCCT CAGTAATTTTTTTTGGTCACCTGTGACATGTCGGGCATTGTACTGGAGGTGGAGAATGCATTAG TGAGCCACACAGATGCAAGGCTCTGCACACTTGTACCTGACATTGTCATTAGAGCTTCTTGATA ACCTTTTGAATAGATCCTACTATTATTTCTATTTTACAGATGAGGAAACTGAGGAACCAGAGAG GTTAAATTAGTTGCCCAGTGTCACACAGCCAGTAAGTGGCAGGACCAGGATTCCAGCCAGGTCT GTCTGATTGCAGAGCCTATGTATCAGTCATCTGCTGCTGCGTAACAAATTACTTCAAAATGGAG TGACTTAACACTGATCATGTCTTATTGCTCAGTTTCTGTGGATCAGGGATTGACAGGGTAGAAT GGGAATGGTTTCCCAGCCCAGGTATCAAACATCAGTGAGCAGAGTCTTCAGATGTCAGCCCCTT AAGATCTGAAGACTCCCTTATCCATGTCTGATACCTGGGCTGGGAAAACTCACACAGCTAGGGG CTAGAACCATTTGGCATGTTTTTTTGTTTGTTTGTTTGTTTGTTTGTTTGTTTGAAACAGAGTC GAACTCTGCTGCCCAGGCAGGAGTGCAGTAGCGTGATGTTGGCTCACTGCAATCTCTGCCTCCC AGGTTCAAGCAATTCTCCCAGCTCAGCCTCCCAAGCAGCTAGGACTACAGGCACGTGCCTCTAA GCCCAACTAATTTTTTATTTTTCAGTAGAGATGGGGTTTCACCATGTTGGTCAGGCTGGTCTCA AACTCCTGACTTCAAGTGATCTGCCCACCTTGGCTTCCCAAAGTGCTGGGATTACAGGCGTGCG GCATCTCTATCTCTAAAAGTCTCTTTAGGCCAGGCGTAGTGGCTTAGGCTTATAATCCCAGGCC TTTGGGAAGCTGAGGTGGGAGGATGACCTGAGCATAGGAGTTTGAAACCAACCTGGGCAACGTA GGGAGACCTCATCTCTGCAGAAAATAGGAAAAATGAGCCAGGTGTGGTGGCATGTGCTGTAGTC CCAGGTGCTCAGGCTGCTGATGTGGGAGGATAGCTTGCATTCCAGCCTGGGTGACAGTGAGCTC CCCTCCCCCTAAAAAAAAAAATCTCTTTAGCGTGAGTCTGTCAGGATGGCCAGACCTGTTAAAT GGAGACTCAGGGTTAAAAAGCGTATGTCCTAAGAGAGAGCTAGGAGGAAGTTGTACTACCTGGA GATCTAACCTCAAAAGCCATGCAATTACTTCCACCGCATTCTATGGTGAAGGTAATTACAGAAA ACTGCCCAGGTTCAAGGGGAGGGAACATAGACCCCGCCAGTCAGTGGAGGAATTTTAGTATCTA TTTTGTAAGGAGAGCATGTATGGATGGTGTATGTCATTGTGTGGCCATCTTTGGAAAATACAAT CTACCGTAGACTATATTCCTAACCTCAAAATGATAGCGTTAAGTTTTAAAAGTTTATTATGGTC TGGGCGCGGTGGCTCATGCCTGTAATCCCATCACTTTGGGAGGCTGAGGTGGGTGGATCAGTTG AGGTCAGGATATCGAGACCAGCCTGGCCAACACGGTGAAACCCCATTTCTATTAAAAATACAAA AAGTTAGCTGGGCGTGGTGGTGCGCATGTAGTCCCAGCTACTCAAGAGGCTAAGACAGGAGAAT CGCTTGAACCCGGGAGGCGGAAGGTTGCTTTGAGCCGAGATCGCGCCACCGCACTCCAGCCTGA GTGACAGATCAAGACTCCATCTCAAAAAAAAAGAAAAAAAAAGTTTATTATGAAATTAATTTCT GTTCATTAAAAAAAAAAAAAAAGAATAGGCCGGGCGCAGTGGCTCTCGCCTGTAATCCCATCAC TTTGGGAGGCCGAGGTGGGTGGATCACCCGAGGTCAGGAGTTCGAGACCAGCCTGGCCAACGTG GTCAAACTCCATCTCTACAAAAATACAAAAATTAGTCCGGCATCATGGCGCGTGCTTGTAATCC CAGCTACTCGGGAGGCTGAGGCAGGAGAATCGCTTGAACCTGGGAAGTGGAGTTTGCAGTGAGA CGAGATCACACCATTGCACTCCAGCCTGGGTAACAGAGCAAGACTCCATCTCAAAAAAAAAAAA AAAAAAAAAAAGAATAGACTTATACAGTAAAAAGCAGAAGTTTCTGTTCTCAACACACCTTTTC CAGAGGTAGTGTAATGTGTGGCGGTATCTTTCCAGACACACCTGATCACATACAAGCGCGTATT TCCAAGTAACAATGGTGAGGGACCACTGTTGGAGGAGGTCCAGGGACACCGTGTTTCCACCCCC ACCTTGTGCTCTTGGTGGCACTGAAATGGTGTGCATAGGTATGTTGAGAGTGACTCTAACAGAT TTTGTGCCAGCGTAATTTCTGAATTATTAGATGTATGATGAAATAGATTTCATAACCATGCCAG GCTAGTATTTGTGTTTTTATTAGGGATGGGGTTTCACCATGTTGGTCAGACTGGTCTCAAATGA AATTATTAGATGTATGATGAAATAGATTTCTTAGTCACCAAGATGGCTCATTTTGGATTGTACT GAAAGTTTTTTTCTTTTTTCCTTTCAGCTTGAAGGTTTATCTATACTGTTCACCTGTGACTAAG GAGTTGTTGTTAACGAGCCCGAAATACAGATTTTGGAAGAAACGAATTGTAAGTTTTATTTTTT TAATAACTTAATTTTTTTTAAGTGGGAAGTATTTTTAGAGGTAGATTGACAAAAACTTTGCCTC AGTTTGTAACATACTTCAGTTATCCACATTAATTAGAATATTGAGTCTCTGGCCGGACATGGTG GCTTACACCTATAATCCCAGCACTTTGGGAGGCCTTGGCGGATGGATCACTTGAGGTCAGGAGT TCATGACCAGCCTGGCCAACATGGTAAAACCCTGTCTCTACTAAAAATACAAAATTTGGCCAGG TGTCGTGGCACACACTTGTAGTCCCAGCTACTTGTGAGGCTGAGGCAGGATAATTGCTTGAACC CAGGAAGCAATGGTTGCAATGAGCTGAGATCACGCCACTGCACTCCAGCCTGGGCAACAGAGTG GGACTCCATCTAAAAAAAAAAAAAAAAAAAAGAAAAAAAAAATTAAGTCTGTTGGCATTGAACA ATATGGCAGAAGTCAACATTTGGTAGTTGTTGATATGTTTTCCTTCTTCCTCAAGAGTGAGATC TAGGTCTCAGTTTTGTTTGCTTAATCTCATTGACCCTCTTGCTAAGATGCATTTTAATATTTTC TATTTTTTGTTTTTGAGATGGAGTCTCGCTCTGCTGCCGAGGCTGGAGTGCAGTGGCTCAAACT CGGCTCACTGCAACCTCTGCCTCCTGGGTTCAAGTGATTCTCCTGCCTCAGCCTCCCAAGTAGC TGGGACTACAGAATCCCACCACCATACCCGGCTAATATTTGTGTTTTTAGTAGGCAGAGGATTT CACTGTGTTGGTCAGGCAGGTCTCAAACTCCTGACTTCAGGTGATCCACCCACCTTGGTTCCAC CCACTTGGTTCCAAGTGGATCCACTCCCAAAGTGTTGGAATTACAGGTGTGAGCCACCATGCCT GGCCACATTTTAATATTTTAGAGTGTAAAGTGTTCATTAACATAATTGCTAAATCCTTTTATTT AAATTGTGGGATAGAGTAAGAAAAATAAACAAATTACAGGCTGTCATAAGGAAGGGATGACAGC TAGAAGAATACAGATAGAATGGGTAACTTTCGGTCTGGCAGAATAAAATGCATCTGTCCAATAT GAGGTAGTCAAGGGGAGGAAAAAGTCTGGTGAATAGAAAATGCAAAGAAGGCAGAAAAAGTCCA ATTATATATGACTATATATAGGAAAGGATTTAATTGTACCTTTGGTCAAAAGACAAATTCTCAG TTTAAGTTAAAAAAATCAGACAAATCTGGCTGGGCCCAGTGGCTCACGCTTGTAATCCCAGCAC TTTGGGAGGCCGAGGCGGGCAGCTCACCTGAGGTCAGATAGAGAACAGCCTGGCCAACAGGGCG AAACCCCGTGTCTACTAAAAATGCAAAAAATTGGGTGTGGTGGCGGTGCCTGTAGTCCCAGCTC CTTGGGATGCTGAGGCAGGAGAATCGCTTGAACCTGGGAGGCGGAGGTTGCAGTGAGCTGAGAT CGTGCCACTACACTCCAGCCTGGGTGACAGAGCGAGACTCCATCTTCAAAAACAAACAAAAAAG TTAGACAAATTCATGAGTATTAGTCTATAAGAGACATAGATAAAACAGAAGGATAAATACAGGT TGAAATTTGAAATTTTGGGGGAAGAAGAAAAAATTACTAACCAATCAGAAGGCCAAAATGTCAG AGTGGCAGTTTTTAATATCAGAAAGTAGACTAGAAGGCAAAGAAAGACAAGGTTTGAAGAGGGT GTCACTGTTAAAAGGAGCCATGGGTCATATGGACGTATGTGCAATTGACAAAATAGCATCCAGC TGAAGTAGAAACTGCGAGAACCTGTCACCCAGTGCTTGATCTGAGGAGAACCACAATGACTTAA CAGAATGTGGGTTCATTACATGGATTAGTTCTTAAATCATTGTGGGAGTTGGCAGAGCAATTTG TCCCAGTGTCACAAAGAGTCTGTTTACTTTTTTTTTTCCTTTTTTTGAGATAGTCTCACTCTGT CACAGGCTGGAGCGCAGAGGCGTGATCTCAGCTCACCGCAACCTCCATCTAACCGGTTCAAGCA ATTCTCCCTGCCTCCGCCTCCCTAGTGGCTGGGATTACAGGCCTGAACCACCACACCTGGCTAA TTTTTGTATTTTTTAGTAGAGATGGGGTTTTGCCATGTTGGCGAGGCTGGTCTTGTACTCCTGC CCTCAGGTGATCCTCCCGCCTCGGCCACCCAAGGGCTGGGATTACAGGTGTGAGCCACTATGCC GGGCTTCTGTTTGCTCTTAAGCTGCTTGCAGCCAGTGCCTCCCTCCTACCCACATTTGGGCAAG CTGACAAAAAGGCCCATGCCTGCCTTAGCACTAAGGCGAAGTTCAAACCAGGCATGTCCAGGCC CAACCCGCACCAAAGTGGAAACCAGGGCTACTTGCTCCTACTCTCTCTTAAGCCACAGGAAACA CTTCTGTCCCCAGCTCAGGGACTGCACTGCCCTCCCCGAAAGTCCTGTGATGTGACTGAAGTTT TCTTCTCATTCTCTGTCGTGTGTGTGCTCGCGTGTGTGTATGTGCATGCGTGTGTGAGTATGCA CACATAGTGTGTGCACGTGTGTTTGTGTGCATGATATCATCCACCTCCACATCTGACCTTTGAT TGAGAAGGGGATTTGTCCTCCCTCTGCAGAGCAGTCACAACAGCAGGGTTGTTCCTGTTGTCTC TGGCATTCAGCTTGAAGTTACTACAGGTCAGCCCGGCCAGCAGTCAGGAAGGAAAGCTGGAAGA GAAGTGGAGGGGAACAGAGACAAACTGGAAGGCAGAATGGCCCACTAGGACAGACCGAAACCCA CTTCTGTCTCTCACTTCCTCTGGCCTCAATAGTGCTGGTCTCCCGCTTTGGCTCTGAAGCACAT GCACCTGCCCCAGGACTCGGAGGAGCTGCACACGGGCACCCAGCAGAAGCTGATGTTGCTGCGG CCCTGCCCCAGACTCTGAGTTAAGCCAGAAGGTCAGCAATGTTCACTAGCTGTTACCATTTCTG GCGCCCTTCAGAGCATTAAAAAATCCCTACTAGTTCACATCTGCCTTCTTAATGTTTACTGTGG GCAACAACATGGAAAGGGGTTCTAGGAAACAGTTCCAGCTTAGGTGAGTTGACATAGTACAAAC AAGGCCACGGCAGAATCAGGGCAAGAAATAGGAAATCAACAATTGTCACTGAAGAGCTTAACAT GCCCCTCCCAGATGCTGAAAGAAGGAGGCAGGAAACAGGATGCAGAAAATGTGTGAATGTGGAC TAATGAACAGAACTTTAAACCCAAGGAAGAAAATAGTATTTTGGGGGGTGCTCATGACACTTAC AAAAACTAACCATGTACTGTGTCACAAAAGAAGGCAATGATGTTGGAGATCAGAAACAAAGGGA CAGCTAAAATCTTCCCATACACGTGGAAACTAAATGCATACAATAACTGACCCTTTGGTTAAAA AGGAAATTGTACGATAAAGAAAACATACAATATGTAGAACTGATATGGCTAGGCTTGGGGGCTC TCATGTGTAGTCCTAGCACTTCGGGAGGCCAAGGTGGGACAATTGTGTGAGTCCAGGAGTTCGA AACCGGCCTGGGCAATACTGCAAAACCCCATGTCTACAAAAAAACCTTAAAAACTAGCCTGGTA TAGTAGAGTGTGCCTGTAGTCCCAGCCACTCAGAAGGCTGAGGCAGAAAAATCACTTGAGCCCC GAAGTTTGAGGTTATAGTGAGCCGTGACTGTGCCACTGCACTCCAGGCTGGCTAACACAGCGAG AGCCTGTCTCAAAATAAATAAATAAATAAAGGAGCTGATGGACAATGGAAATGTGGCATGTCAG AATGTGTGGAACATAGCTAAATTTGTCCTTGAAGGGAAATTGATAGCATTAAATAGATATATTA GAAAAGAGGACTAGCTCAGTGGCTCACACCTGTAATCGCAGCACTTTGGGAGGCTGAGGTGGAG GGATCACCTGAGGTCAGGAGTTCGAGACCAGTCTGGCCAATATGGTGAAACCCCATCTCTGCTA CAAAACATTAGCCAGGCATGGTGGCGGGTGCCTGTAGTCCCAGCTGCTCAGGAGGGTGAGGCAG GAGAATTGCTTGAACCTGGGAGGCAGAGGTTGCAGCAAGCTGAGATCGTGCCACTGCGCCCCAG CCTGGGCGACAGAGCGAGACCCTATCTCAAAAATAATAAATGGGGAAAAACCCATTTCATACAT GAAAATGTAAGAATCCTCATAAAGACAGTAACTGAATCTAGCAGTGTTAAATAGTACATCATGA ATAAGATGTTTCATTCCAGAAATGCAAAAATACTTTAACACCCAAACCTTAGACACTGTAAGTT TTAGGACATTAGTGGACTAAAAAGGTGAAAAATCACATTGATCTATTCATCAGATACTTACTGA ATGCCTCTTATGTGCTAGTCTCTGTTTTGATGGCAGGGGGAAATGTACCAGGGAGCGTTCGGCA GCACTTAGAACCAGTGCATGAGGCTGGGTGTGGTGGCTCACGCCTGTAATCCCAGCACTTTGGA AAGCTGAGGCAGTTGATCCTGAGGTTAGGAGTTGGAGACCAGCCTGGCCAACATGTCAAAACCC TGTCTCTACTAAAAGTACAAAAAACTCAGCCTTGCGTAGTAGCGGGCGCCTGTCATCCCAGCTA CTTGGGAGGCTGAGGCAGGAGAATCGCGTGAACCCAGGAGGCGGTGGTTGCAGTGAGCCGATAC CACACCACTGCGCTCCAGCCTGGGTGACAGAGCGAGAATGCATCTGAGAAAAAAAAAAAAAATA AAAGAACCGTGTATGAAGCATCCATGTCACAGACCCATCCAGACTGTGTTCTGAGGCACAAAAG TTAGGACACAGGACCACGTTTTTACAAAGACTCAGAATTCAGAGAGAGAGGGGAATGGGAGTGG TAGGGATGGGGAGATGAAGGAGGAAAAATGAATTCATGGAAACAGAATTGTGTCAGAGGATTAT ATGCATTTACAAGGCGTTTACTCCGTATTACCAAATCTGCCTCAAGACAGGTATTATTTTCTTT ACAATTTTTTCTAACTGTTAAAATATTTATTACAATGTAATCGGAATTGTTTATATAGAGAGTC TGAAACTTCTCTTTGCCCCATTTCTGTGTTTCAGACAGCAAAGGCATATAAAGCCATGAAAAAC TGCTATATACATGGTCTCTTATTTTATTTTTATAGATATCTATTGAAATCGAGACTCCTACCCA GATATCTTTAGTGGATGAAGCATCAGGAGAGGTAACTAAATATTAAATATTGATTTTTTTAAAA AAATGTGGTGCTAAAATGATTGTTTATATTTCTCTTTGATTTTGCAGTCAGATGCTCCACCCCT CAGCTATACCCTCAATCTTTCTCTTTGATTTTGAATGCTCATTTAACCATAAATAAAAATCTAG TCATTGAGTGGGGTTTTAGGGGCAAAAAAATCCCTTTGTGATTGTGTAAGTCCATTTGGGCTGG ACTCACAAAACTACCGTAGACTGAGTGGCTTATACAATAGACACTTGTTGCTTAGGGTTCTAGA GACTGGAAATCCAAGATCCAGTCTCCAGCAGATTTCGTGTCTGGTGAGGGCCCACTTCCTGGTT CTTTTTTTTTTTTGAGACAGAGTCTCACTCCGTCACCCAGGCTGGAGTGCAGTGGTGTGATCTT GGCTCACTGCAACCTCCACCTCCTGGGTTCAAGCGATTCTCCTGCCTCAGCCTCTCTAGTAGCT GGGATTACAGGCGCCTGCCACCACGACCAGAGCCCAGCTAATTATTGTATTTTTAGTAGAGAAG GGGTTTCACCATGTTGGTCAGACTCATCTTGAACTCCTGACCTCAAGTGATCCGCCTGCCTTGG CCTCCCAAAGTTCTGGGGTGACAGGCGTGAGTCACTGTGCCTGGCCACTTCCTGGTTCTTAGAT GCTGTCTTTTTCCCTGTGTCCTCCCATAGTAAAGGGGCAGACAAGCTCCCCTGGGTGTCTTTTA TAAAGGCACTGATGTCACTCACAAGGCTTCTATGCCCAATAACTAATCACCTCCCAAAAGCCTC CTAATAAAACCACTTTGGGGGTTAGGATTTCAACATAGGAATTTTGGGGAGGGACACGAACATT TAGTCCTTAACAGTGATGTATTTATTTCCCATGTTGTAAAGGATTGGGCATGGCTTATTTTTTG TCACATTTGTTCCTTATTACATGCTAATGATGGGAACCCTGGTGTTGATATTACTACATGATGT TATTGTCACATTTACTGAGTTTTATAATGCTCAGAATTTAAAATGGTGATTAATATTTTTGCAG GTAATTCATGAATATTGTACTTTTTTTCTGAACCCTTATTCAGAAAAGGGGCTCTGCCAAGTGG AAAAAAATTATTTTTCATCATTAAATTTTGAGGTAGTACTTTTGTGAATGTATGGTTTTAATAA GTAGGACTATAGACATACAGCCCCCCTTTTTTTAACCTTTACAGCTGGTAGGTATTTTCCTATT TTGGTTAATATTGGCTTTGTTGCTTGATTATAGCACACTGCTTTGCCGTGTTTAACTTTGAGGG TGTGTTGTGTTGTTGAACAGAAACTGACCTTTTCAGATATTTCTTCTTTGGTGAAGATCAGACA GTTGAAGTTGAAGTATTCTTCCCATCAAATTATCCTGAGGGAGGACTACAGAGCCAGTTTAGTG AGGATTAAAAAGGAAAAAAAAAATAGGTGAACCTTTGTAAATGCCATCCTGGACTCTGCCAACT GCTTTTCCGGGGAATACTGTGGTGGTCTGTGGCCTTGTCACAATCAGGGATATTGGTGAAAGGC ATTCCCTGAACTGGGGGCCGACAGCAGGCTGACTTTTGAGCAGTCCTGCCACCACTTTGATTTT TTATGTTTCTTCCTGTGTGCCATGACTTTTATGCATTGTTTATCCAGCTCCAACCAGGGGGAGA CCCACTCGAAAGGGTCCTCCAGAATGAATGGAGACTTCCATGAGGAGTCCCTGTCACTGAGCAG TGACCTGGTGTGTGCAGAGCTCTCCCCACTTACTGATGGCTGGAGAGGCAGTAGTGCCTGCAGG TCTTGCCCTTGCCGAACAGTATGATGTGCAGTGTGAATCGGGACCAGGCCTCATCCAGGCTTTA ATCTTTTTTTTTTTTTTTTTTTTTTTTGAGACTGAGCCTTACTCTGTCGCCCAGGCTGGAGTGC AGTAGGGCGATCTTGGCTCACTGCAACCTCTACCTCCTGGTTTCAAGCGATTCTCTTGCCTCAG CCTCCTGAGTAGCTGGGATTACAGGTGCTGCCCACCACCATGCGCAGCTAATTTTTGTATTTTT AGTAGAGACAGGGTTTCGCCATGTTGGCCAGACTGGTCTGAAACTCCTGACCTCAAGGGATTCG TTCACCTTGGCCTCCCAAAGTGCTAGAATTACAGGCATGAGCCACCGCACCTGGCTCAGGCTTT AAAAATTGTTAAATAGTGGCCGGGCTTGGTGGCTCTCACCTGTAATCCCAGCACTTTGGGAGGC CGAGGCAGATGTATCACTTGAGGTCAAGAGTTCAAGACTGGCCTGGCGAACATGGTGAAACCCC ATCTCTACTAAAAATACAAAAAATTAGCCAGGCGTGATGGCAGGCGCCTATAATCCCAGCTGGG GAGGCTGAGGCAGGAGAATTACTTGAACCCAGGAGGCAGAGGTTGCAGTGAGCCAAGATCACAC CATCGCACTCCAGCCTGGGTGACAGAGTGAGACTCCATCTCAAAAAAAAAAAAAAAAAAAAAAG TAAATAGCTTTATTGAGATAGAAATCGAGTCACACACTTGTGTATCCATCACCACAATCAATTT CAGAATATTTTCAGCACCCCAAGGGAAGAAGCCTTTAGCGATCGCAATCCCTCCCTATTCTCTC CTTCCCCAACCCCCGGCAACCACTACTGTATTGGACTCTCTGTCTCCATGGGTTCACCTATTCC GGATATTTCATATGAGTGGAATCATACAACATGTGTTCATTTCTTATCCGGCTTCTTTCACTGA GGATGTTTTCAAGGATCATCCATGTTGCAGCACGTGTCGGTTCTTTTTATGGCCAAATAATATT TCATTGTATGGCTAGACCACATTTTCCTGATTGATGCATCAGCTGATAGACATTTGAACTGGTT CCACCTTTTGGCTAGTATGAAGAATGCTGCTGTGAACAGTCAGGCACACATTTTTGTGTGGCCA TCGGTTTTCGCTTATCTTGGTTCTATAACTAGTGGTGAAATTGCTCAGTCCCATGGGAATTCTG TTTGTTGAGTGGACAAGGATTCCACTTGTTTCTAGGATTTGGAGTGTGAGGAAATTGGGAGAAA AGGCACATTGTTAAAAGGTACATAAATGTGTTCTGTGAAGGAGGGCTTTGTTGAGCTAGGTCCT AATGATAACTGCTTTCCATTACTATTTTTTCTTTATTTTCTTTTTAGAAGGAAGAGATTGTTGT GACTCTCTTACCAGCTGGTCACTGTCCGGGATCAGTTATGTAAGGGGGTCATTTATTTTGTCAT TTTATTATATGTAGACACATATTGTATTTGTAGAAATAAATTTTTAGGGTCTAAAATTAATAGG GGGCTGGGTGCAGTGGCACATGTCTGTAATCCCAGTGCTTTGGGAGGCTGACGCGGGAGGATTG CTTGAGCTTGGGAGTTGGAGGCTGCAGTGAGTTTTTTTTTTAAAAAAAAAAAAAAAAAGAAAGA AAGAATACATAGAGGGAGATTTGATTTTTTTTCTAGTCATTTAAAACACATTTGTTCCCAAATT GAACTAGGGGGACTGAGGTGAAGATCAGATTTGAAACGTTTCTTATAAAATGGAAGTCTTCATG GCCAGGTGTGGTGGCTCACACCTGTAATCCCGGCACTTTGGGAGGCCAAGGCAGGTGCATCACT TGAGGCCAGGAATTCAAGACCAGCCTGGCCAACATGGTGAAACCTTGACTTTACAAAAAGTATA AACATTAGCCGGGTGTGGTGGCACACCCCTGTAGTCCCAGCTACTGGGGAATTGCTTGATCCCA GAAGGTGGAAGTTGCAGTGAGCCAAGATTGAGCCACTGCCTTGCAGCCTGGGGGACAGAGCAAG ACTCTTATCTCAAAATAAAAATAAATAAATGGAAGTCTTCAGCAGCTGTTTCCCCAGTGACCTT GTATTTTATCATCACGTGTATTTCTCTCTCCATGAGCAAGAATGATCTCAACATATAATTGAAA GTGCTAACATATCACAAGGAACATCTATTACAAACTGGGTAGCATCTCCATTCTGTTATTTTCT ACCCGAGGGAAGAGGTGACAGCTGAGTGCCTGGTGTGGTTCAAATTACTGTGGAATTCCATTAC CATTGTATTGTAATGGATATGTTTGCAGGAAGCATTTAGTATGCAGCTCACATGTATTTGCTTT ATTGGGAGTTTATATGAGACTCAGAAGTCACTGGGATATATTTCTTTTTCAGGTTTTTATTTCA GGGCAATAATGGAACTGTCCTGTACACAGGAGACTTCAGATTGGCGCAAGGAGAAGCTGCTAGA ATGGAGCTTCTGCACTCCGGGGGCAGGTACTGGGCCTCGTATAGGTTTTATTTTATTTTATTTT ATTTTTGTGAAATGGAGTCTTGCTGTGTCGCCCAGAGTTCAAGCGATTCTCCTGCCTCAGCCTC CCAAGTAGCTGGGATAACAGGTACGTGCCACCACGCCCAGCTAATTTTGTATTTTTAGTGGAGA TGGGGTTTTGCCATGTTGGGCAGGCTGGTCTTGAACTCCTGACTTCAGGTGATCTGCCCCCCTT GGCCTCCCAAAGTGCTGGGATTACAGGCATGAGCCACTGTGCCTGGCCTCTTGTACAGTTCTTC TGTGTATGACTGAATAAAGTTTTATTGCTCTGGCCGGGTGTAATCCCAGCACTTTGGGAGTTCT GGCCTGTAATCCCAGCACTTTGGGAGGCTGAGGTGGGTGCATCACTTGAGGCCAGGAGTTCGAG ACCAGCCTGGTCAACATGGTGAAACCCCGTCTCTACTAAAAAATACAAAAATTAGCAAGGTGTG GTGGCACAAACCCATGATCCCAGATAGTTGGGAGGCTGAGGTAGGAGAATTGCTTGAACCCGGG AGGTGGAGGAGGTGGTAGTGAGCAGACATTGCACTTCAGCCTGGGCAACAGAGCGAAACTCCAT CTCAAAAAACAAAAAAAGTTACACATAATTTATATCACATTGGATGGCTAACATCAATTTTTTT TCTTTTCAGAGTCAAAGACATCCAAAGTGTATATTTGGATACTACGTTCTGTGATCCAAGATTT TACCAAATTCCAAGTCGGGTAAGTCTGCCTGGAGGAACAGGGTTATCATCTGGGTGTGCCCGTG TTTTTAGTAGGAAGTTTGTAGGGTGACAGGTCATATCCTAACTGTCCCCGTAGGTGTGAGTACC TGGGACTGTTGGGAAGGAAAAGGCTATGTGCGGCTCTCCACCTGTTAAATGTCTCTTTAAAATC CTGTCTAGGAGGAGTGTTTAAGTGGAGTCTTAGAGCTGGTCCGAAGCTGGATCACTCGGAGCCC GTACCATGTTGTGTGGCTGAACTGCAAAGCGGCTTATGGCTATGAATATCTGTTCACCAACCTT AGTGAAGAATTAGGAGTCCAGGTATGGTGACTGTTCATTCTTTTCTTTTCTTTTTTCTTTTTTT TTTTTTTTTGAGAGGGAGTCTTGCTATGTTGCCCAGGCTGGAGTGTAGTGACGCGACCTCGGCT CACTGCAGCCTCCACCTCCCGGGTTCAAGCAATTCTCCTGGCTCAGCCTCCTGAGTAGCTGGGA TTACAGGCGTGAGCCACCATGCCTAGCTAATTTTTGTATTTTTAGCACAGACGACATTTCACCA TGTTGGCCAGGCTGGTCTTGAACTCCTGACCTCAAGCTATCTGCCTGCCTCGGCCTCCTAAAGT GCTGGGATTATAGGCCTGAGCCAGTGTTCCCAGTCTGTTCATTCTTTTCTCTTGCTCCCTTCCA TCCTCCCAGCTCACCTTTCCTCCCCCTCCTCGCCTGCTAAATAACTGCAAACAGGGACAGATGG AAGCACCCTAACAAGACGTGTCTGCAGCAGAGGTTCGCGGGCCCTCTGAAGGAATATATCATCT TAGTTCAGTCACATCCTCCTGGGAGAAAATTGACAGAAGCCAAAATGGCTTACAAGAGCCTTCA GTGAAATGCCGCATAGACAAAGTATTTTTCCCAAACTTTGGGTCATGAAATAAATTTAGTGATT GTGACCAGCATTGAAAATAAATTTGAACAAGGAGATATGGCAGTGGATTATTTGCAGTACATGC TCCTCTGTTGTACATCATGTATATGCCTTTAAGGTGATTCTTGATTTTTTTTTTTCTTTTTTGA GACTGTCTTGCTCTGTCGTCCAGGCTGGAGTGCAGTGGCACGGTCTCAGTTCACTGCAACCTCT GCCTCCTGGGTTCAAGTGATTCTCTTGCCTCAGACTCCCGAGTAGCTTGGATTACAGGCCTGAG CCACCATACCTGGCTAATTTTTGTATTTTTAGTAGAGATGGGGCTTCACCATGTTGGCCAGGCT GGTCTCGATCTCCTGACCTCAAGTGATCCACCGGCCTCCGCCTCTCAAAGTGCTGGGAATACAG GCATAAGCCACAGCACCTGGCTGAGGGTAGATGATTCTTGATTGTTTTTGTCTGTGTGGATTAC TGCTTTATTCCCAGCATTTAGAATAAAGCTCGACACATAGTAGGTGTACGAGGAATATTAACTG AATTTCTCTTGAAGGACTGAAGGACAACATTAACATCATTAAATGACATCCCTGAGCCGAGTGT CCATAATTGTTCACTGACGTCAGTGATGGCAGCGATCCTGGCCAGTCAGCCTTGTGCCTGTTGA CATGCTGGCGGAATACCAGAGTGCACTGAATAGCCAAAAACTACTTTTCAAGAAAGAAGAGAGG GTTAATTCACTAACTGGGTGTTTTGCCCTGAGTAATTAACCTTGAACAATTTATAGGAAATACA TTTCACATAATTTGCATGTATGTATTATTTGCCTTAGGTTCATGTGAATAAGCTAGACATGTTT AGGAACATGCCTGAGATCCTTCATCATCTCACAACAGACCGCAACACTCAGATCCATGCATGCC GGCATCCCAAGGTACGTGTGCAAGTGATTCCTCTCGTATTGTTTGTGTAATCTATGAAAAAGAA GAAAGGTCAGGGCTTCCATTTATAGGCTCTTCGCTTTACAAATGTAAAACCTGAGGCTGCAATC CTAAGTTGTTAGCTCAAGGTCATGGAACTGTACATTGCCATATTCCATGACCACACTTTTCGTC ACTAGTAAATAGACACAGATCTGTACTTTTTTTTTTTGAGATGGAGTCTCACTCTGTCGCCCAG GCTGGAGTGCAGTGGTGCGATCTAGGCTCACTGCAAGCTCCGCCCCCTGGGTTCACGTGTTCTC CTGCCTCAGCCTCCTGAGTAGCTGGGACTACAGGCGCCCGCCACCATGCACGGCTAATTTTTTG TTATTTTTACTACAGACGAGGTTAGCCATGTTAGCCAGGATGGTCTCAATCTCCTGACCTCGTG ATCCGCCTCCCTCGGCCTCCCAAAGTGCTGGTACTACAGGCGTGAGCCACCACCCCCAACCAGA TCTTTATAGTTTTCTGATGAAATCTATTCATACACGTTTGATAATTCAAATTTATTTGTAATGA AATCAGTAATATATTATAGCTTATAACTTAAACATTTGTGCTATTTATATATGTATTTATATAT TTCGAGACATTCTCCTTCTGTTGCCCAGACTGGAGTGCAGTGGCCCACTCTTGGCTCACTGCAG CCTCCATCTCCTAGGTTCAAGTGATTGTCCTGCCTCAGCCTCCTATGTAGCTGGGACCACCGAC ATGCACCATGACTTCTGGCTAATTTTTGTAATTTTATTGATTTATTTATTATTTATTTATTTTT GAGACGAGCCTTGCTCTGTTGCCCAGGTTGGAGTGCAGTGGGGCCATCTTGGCTCACTGCAACC TCTGCCTCCTGAGTTCAAGCGATTCTCCTGCCTCAGCCTCCTATGTAGCTGGGATTACAGGCAT GCACCACCATGCTTGGCTAATTTTTGTAAGTAGAGATGGGGTTTCGCCATGTTGGCCAGGGGGG TCTTGAACTCCTGATCTCAAGTGATCTGCTCTCCTTGGCCTTCCAAAGTGTTGGGATTACAGGC ATGAGCCACTGCGCCCATCCTGTGCTTTTTGAGACTCATGACATGAGCGTGTTTATAAACTTTT TCTTCTACTTGAGATAAATATCTAGACATAACTTTTTTTCACACTTTAAAATAGTTTCATGTCT TGATGGTCCTATTTCTAATGGATGTTTCCAGTGTCTTTGCAAGTCACATGTCATTTGTCTTCTT TTGTTTTTTGTTGTTTTGTTTTTTTGTTTGAGATGGTCTCACTCTGTGGCCCAGGCTGGAGTGC AATGGTGCCATCTCGGCTCACTGCAAGCTCTGCCTCCCACATTCAAGCGATTCTCTTGCCTCAG CCTCCCGAGTAGCTGAGATTACAGGCTCCCGCTACCACACCTGGGTAATTTTTGTATTTTTAGT AGAGACAGGGTTTCACCATATTGGCCAGGCTGGTCTCGAACTCCTAACCTCGTGACCACACACC TTGGCCTCCCAAAGTGCTGGGATTACAGGCATGAGCCACCACACCCAGCCTCATTCGTTTTCTA ATGCCAACACAGAACCTCCTTCTCTTGTCAAACGCTGAGTACAAGACTTTCATTTTGAATTTGC TTTAAAAAATATTGTTTCAATTAAAATTATTAAGGCTAATTAGTGATCTTTAAATGTAGTGGTT TGAGTGATCATTATTTTTCTCTAAATTTTAAAATACCTTAGCATTAAATCCTGTGTAATTTTTA AAGTAAACATTGCATTTATTCATTTAGATCACTATTATTGTAGTAATAATGGTTCCATTAGCCA AAAGCCTAGTTGCCTAGCCCTTACGATAAAGCATAATTTCAAACAAGAGAGAATTCTGATCCAC AGCATGGAATGTTTTCCTGTAGGCCACGGTGAGAGCTGCAGTGTAAATTATTTTTGCTGATTGG TAAGCTGCATATTCTATGTTGCATTCAGGGATTTATTTCTTCACTTTGTGTGCATGTATGCACA TATAAATACACATATATATTCACATATACAGACACGTCCAGTGGATTCTTGGATGGATAAAAAT GTATACATAAAACGTAAACCGGCCGGGTGTGGTGGCTCATGCCTGTAATGCTAGTGCTTTAAGA GGCCGAGGCGTGTGGATCACTTGAGGTCAGCAGTTCGAAACCAGTCTGCTCAGTGTGGCAAAAC CCCGTCTCTAGTAAAAATAAAAAAATTAGCTGGGCATGGTGGTGTGTGCCTGTAGCCCTAGCTA CTAGGGAGGCTGAGGCATGAGAATCACTTGAACCTAGGAGGCGGAGGTTGCAGTGAGCCAAGAT GTCACCACTGCACTCCAGTCTGGGTGACAGAGCAAGACTCTGCCTCAAAAAAAACAAACAAAAC CCATAAACTTAGTGGCTCACATCTGTAATCCCAGCACTTTGGGAGGCCAAGGCAGGTGGATCGC TTGAGTCTAGGAGTTCGAGACCAGCCTGGGTAACGTGGTGAAACCCCGTCACTACAAAAAATAC AAAAAAAAAAAAAAAAAAAAAAAAAAGGTGCTGAGTGTGGTGGTGCATGCCTGGAGTCCCAGAT ACTTACGAAGCTGAGGTGGGAGAATTGCTTGAGTTTGGGAGGTGGAGGTTGCAGTAAGCCAAGA TTGTACCACTGCACTCCAGCCTGGGTGACAGAGTGAAACCCCGTCTCAAGTAAATAAATAAAAC ATACACCTTTTTGTCCCTTTTTCTGTTGGACTCATAGTATTGGGCCCCTTGCCCCATAAATCCT TGAATTGGCAAATTTCTTTTTGCTGTGAATTTTCTCACATCCCACAAAGTAGCTTAGTTAGTAA TTCCTTTGCTGTCAGGGCTACTTTCCTTGAGATGCTATTTCTAGCCGCTTAAAAGATTTTTTTA GGTCACGCACTCCTTTAGAATATTAACAGGTAGGTCCACAGCTCATAGAGTCCACTCTTAACTC TAATCTGCACCTTCCTAAGAAACAGCACCAAAGGCACCCCAAAGAAATTTGAGTGGGATGGAAC GTTAATGGTTTGGAAGGTTCTGGATTTCAAAATAATGACTTTGGAAAAGTTGTCCCATTTTTTT TCAACCTTTTGAAAACACTTGTATTTGTTAGTTTTTTTCCCTCCAAATTTATTTTGAAAACTTT TTAATTTGAATTAATGAATTTATTTTATAGAGTCTTGCTCTGTCACCCAGGCTGGAGTGCAGTG GTGCAATCATTGCTCACTGTAGCCTCGACCCCCCAGGCTCAAGTGATCTTCCTGCCTCGGCCTC CTGAATAGCTGGGACTGCAGTTGTGTACCACCCACCTGGCTAATTTTTACATTTTTTTGTAGAG ATGGAATCCCACTATATTGCCCAGGCTGAGATCTTTTTTTTTTTTTTAATTAAAAAAAAATGGT TTTTTGAGATAGAGTTTCGCTCCGTTGCCCAGGCTGGAGTGCAGTGGCGCAATCTGGGCTCACT GCAATCTCCACCTCCTGGGTTCAAGCGATTCTCCCGCCTCAGCCTCCCAAGTAGCTGGGATTAC AGGCATGCGCCACCATGCCTGGCTAGTTTTGTATTTTTAGTAGAGACAGAGTTTCACCATGTTG GTCAGACTGGTCTTGGACTCCTGACCTCAAGTGATCCACCTGCCTCAGCCTCCCAGAGTGCTGG GATTATAGGCATAAGCCACCACAACCGGCCCTGAAAACTTCTTAAACAGTAAAGTTGTAAGACT GGTACAAGGGTCTGGGCCCAGTGGCTCTCGCCTGTAATTCCAACAGTTTAGGAGGCCAAGGTGG GCAGATCTCTTGAGGTCAGGAGTTCGAGACCAGCCCAGCCAACATGGTGAAATCCTGTAACTAA AAATAGAAAATTTAGCTGGGTGTGGTGGTGTGTGCCTATAATTTCAGCTACTTGGGAGGATGAC ACATGAGACTTGCTTGAACCCAGAAGGCAGAGGTTTTAGTGAGTTGAGATGGTACCACCACACT CCAGCCTGAGTGACAAAGCGAGACTGTCTAAAAAAAAAAAAAAAAACACCATACACCCTTCGTT TGGATTTGCTGCGTTGCCAACACTTTGCACCTCTCTTCCTCTGTCTCTGTACTTATAACCAACT CCCCACTCCAAACCAATTGAGAGTAGTTACAGACTCCATGGTACGTCACCCCAAATCCTTCAGC CTGTGGCTCTTGAGAATAAGAACATTTTCCTATATAACCACAGTACAATACCCTTCCTCAGAAC ATTTTGTGTTCATATAGTACTATTAGCTGTTACACAGTCCGTGTTCAGATGTCCCCAGTTCTTC CCATAGTGTCCTTTATAGCTTGTAGAATAGGGGGACAGGGGCATCCAGGATTTATTTGAGGGTC GTCCATTGCGTTCAGTCAGGTCTAAAGGGTCTCCTTTGATATATAGATCGTTTGTCTAGCCTTT TGCTTGTCTTCACATTGATGGTTTTGAAGAGTCCAGCCCAGTTGTTTTGCACAATATTCCCCAA TTTGGAATTATCTGATTGTTTCTTCATGTCTACATTGTTTTGCTGCTTTTTTTTTATTTTTTAT TTTTTCGTGTCTGGAAACTTTTCTACTTTTGTTTTTGAGACTCTGCCTACAACAGATTTGTAGA AAATGTAGAACTGTTTTTCTATGCTTTTTATCTTTTTTAGGCAGAGGAATATTTTCAGTGGAGC AAATTACCCTGTGGAATTACTTCCAGAAATAGAATTCCACTCCACATAATCAGCATTAAGCCAT CCACCATGTGGTTTGGAGAAAGGAGCAGAAAAACAAATGTAATTGTGAGGTAAGAGAGCAATAT CATAGGTCTTCTGAGAGAAACTTTGAGTAAATTGTCTGATTTAATTTCATTTAAGCACAGTCTA GCCTAAGCCCAAGAATATAATTATATATTATAATTAATTTCTTAAATTTAAATTTTATTTAAAT GGAGGGGATGCTACTCCCAAACCAGTTACACTCCCATCAGCTGGTGTATCCTGAGGTTCCCTCT GGGTAGGTTGATGAGATGGTTGGAGACTGAAGGCATCTGAGTGCTTGGCTTAGAGTAACAAATT GATGTCATACAGAACAGAACCCTTGGTGGAGCAGAGGAGTGACTATCATGATCACAATATTTTA GCAATATTTCCTTAACTTTGGCTGTTTAAAATTTCTGCAACAGGTCCCTCCCTCCCTCCCTCCC TCTCCTCCATCCCTTCTTCCCTCCCTCTCCTTTCTCCCCCCCCACTCCCTCCCTCCCATCTGAG TGCTTGGCTAAGAGGAAAAACTGATGTCAGAGAGAACAGAACCCTTGGTGGAATAGAGGAGTGA CTATAATGATCTTAATATTTTAGCAACATTTCCTTAACTTTGGCTGTTCAGAATATCTGCAAGA GGTCCCTCCCTCCCTCCCTCCCTTCTTTTTTTTTTGTGTGGAGAAAGAATCTCACTCTGTCACT CAGGCTGGAGTGAAGTGGTGTGATCTCAGCTCACTGCAGCCTCTGCCTCCCGGTTCAAGTGATT CTCCTGCCTCAGCCTCACTAGTAGCTGGGATTACAGGCATGTACTACCACCATGCCGAGCTAAC TTTTTGTGTTTTCAGTAGAGACAGAGTTTCACTATGTTTGCTAGGCTGGTCTCGAACTCCTGAG CTCAGGCAATCCGTACGCGTCGGCCTCCCATAGTGCTGGGATTATAGGCGTGAGCCACCACACG CGGTCTACAACAGGTTTCCACTTCTGGAAAAGGTTCCCTGCTATCCCAAGAAGAAATTCCTGAT TTAGGGTGATTTCGACACTTGCTGCTGAAGCGAGCCCATTAGAGTGGTTTCATGCTAGAATAGC CTAAATGAGAAGGGCCAGCTTTGCTTAGTTTTAGTTTTGCTCAGTGATCTTTTTATTTTGTGTT TTCACTTCCCTTTAGGACTGGAGAGAGTTCATACAGAGCTTGTTTTTCTTTTCACTCCTCCTAC AGTGAGGTAAGAGGATCCCATATACTCATAACCCTTATCGCTCAGTGTTCTGCAGCCTTGGTAG TTGACAGGTAGTCCCCTGACTCTCAGAAGCATCTCTGTTTCTATGTAAGTTTCATTTCCTTTTA GTTTTTTTTTCCTAAATGCAGTTCATCCTCATTATTCATGGATTCCTTTTTTTTTTTTTTTTTG GTTGAGACAGTGTTTTACTCTGTCGCCCAGGTTGGGGTACAGTGGTGTGTTCTCGGCTCACTGC AACCTCTGCCTCCTGGGTTCAGGTGATTCTCCTGCCTCAGCCTCCCGAATAGCTGGGACTACAG GTGCCCACCACCATGCCCAGCTAAAATTTTTGTATTTTTAGCAGAGACAGGGTTTTACCACATT GGCCAGGCTGGTTTTGAACTGACGTCAGGTAATCCGTCTGCCTTGGCCTCCCAAAGTGCTGGGT TACACGTGTAAGTCACTGCACCTGGCTTCATGGATTCTATTTTTATGTGTTGGCCTACTCACTG AAACTGACCTGTGACCTCAGTATCAATATTTACAGTGCTTTTGTGATCCTTTGTGGACTTGTGG AGAGTGGTGAAAATTTTGAATCACCTGACGTGCACGTTCTCGGCTCAGGTAGAACAAGGCAATG CTCTGCCTTCTTTCAGCTCTTACTCTGTCAACAAGTGTATCAGTCTGTTCTCCTGCTGCTCTAA GGACATGCCCGAGATGGGTATGAGGAAGGAAAGAGGTTTAATTGACTCATAGTTCCGCAGGGCT GGGGAGGCCTCAGGGAATTTACAATCATAGCAAACACATCCTTCTTCACATGGCGGCAGCAAGA AGTGCAGAGTGAAAGTGGGGAAAAGCCCCTTATAAAACCATCAGATCTCGTGAGAACTGTCATT AGAACAGTATGGAGGTAGCCACCCCCGTGATTAAATTGCCTCCCACTGGTCCCTCCGACACATG GGGATGATGGAAGCTACAGTTCAAGATGAAATTTGGGTAGGGACGCAGCCAAACCATATCGAAA GTTTCCTTTTTGCCATCTATTAAGTGCCATGTTTTTCATATTTTTGTGCTTTTTGTTGGTGATC TTATTTAAATGGTGACCAGTCATAATACTGAAGTCCTATCGAGTGTTCCTAAGCACGGGAGGAC TGTAACGTGGCTTCTAGAGAAAATATGTATGTTAGATAGGCATGGGTTATAGGGCTATTGACCA TGAGTTCAATGTTAATGGATCAAAGTGTCTATTAAATAAGGTGTCTTTCAACAGAAACACACAT AAAACAAGGTTATGTATTAATTGGCTGGTGAAAACGATGTCACCAAAGGATGGCAGGAACCCTG TATTTTCCCTAGCAGCAATGGCTCAGTATTTGCTAATTCAGCATTTATGGTGACTATAATTTAT AGAGTATAACTACTGTGAATAAAGAGAATTGGCGCTATTGATGCCTTATTTTAAGGCAGGCATT TGATAAAAGGGAGTCAACTTATATAAATGAGAGGGGGTGCTCCTTTATTGGGTGTCTCTTATCT CCTTGGGGCCATTTCATCTCTGAGAAGTAGTAGTGAACCATTTCTGGTATAGGCTTGACTTTAC TTTTTTTTTTTTTTTTTTTTTTTAAATCCTTTATTCCCTTCAAAAGTCTCAGATTTCTACCAGC CTCAGCTTTGTGCAAATCAAATCGGTGTTGGGCGGGCAGGTAATGATTTCTATTTGCATGCCTC CTGTGAAGGTACAAAAGATACTGTTTGTGAAAACTATTTAAAGAATAGATCTTCCTGCCTTTCC ACTGTCTTAAAGTAGCCCTTTTATTTTTATGTAGAGTTATTGGCAATTCTTGGGTTTCTGCCTC TTTCAGTTTGGTGGGATACTAATAATTACATTGGGTTCTAGTCTGTCCATTTGCAGAAGGGCAT AAAAGTCTTTGTGTTCTCATTATCAACTTAGTAATGGATGATTTTTTTTTTAATTTTTTAATTT TTATTTATTTATTTTTTTGAGATGGAGTCTCGCTTTATTGCCCAGGCTGGAGTGCAGTGGCGTG ATCTCGGCTCACTGCAACCTCCGCCTCCCGGGTTCACACCATTCTCCTGCCTCAACTTCTTGAG TAGCTGGGACTACGGCGCCCACGACCACACCCAGCTAATTTTTTGTATTTTTAGTAGAGACGGG GTTTCACCGTGTTAGCCAGGTTGGTCTCGAACTCCTGACCTTGTGATCCACCCGGCTCGGCCTC CCAAAGTGCTGGAATTACAGGTGTGAGCCACCACGCCTGGCCTGGATGATTTTATTGACTGTTT CACCAGATACCAAGCTAAGCACTTCACATGCATAATCTCATTTATACTTTTAAATGAAGAATCT AAAATTAGAGACATTAGGTAACTTGACTGAGATCACAAGCTCACCAATGTCTAATAAGAGACAA AGCTGAAGTTCCTCTAGGTTGTAGAGATGTTTTGAGGAATAGTGACAGAGTTCCTCTGTTTAGC ATTCTGAACTTTGCAAAAAGTCAAGGTATTCATGAAGTTTTTGCATGTAATTGTTTGTTTAGAA TTAATCATTGGGAGAGGCAGTCTATGTGCACAGTCTTTCAACCCTCACTGGCCACATAAGAATG GGACACTTCCTTATTGAGAGAGAGCGCACGCGAGTGAGAGAGAGCAAGCACTCCCGTTAGCGTG AGCACACAGCCTGCGGCAGCTCAGTACCTTGTGTGGAAACATCTTTCTCTGCTTCGTACTTGAT GTGTGTCCCTTTGTTCTACTTAAGCCTGTGTGTCAATGGCCCTTAGGCACACCCCAGCTGTCCT TATTTCAGACAGCATGATGGGGGTTCCTTCCTGTGTGGCAGGAGAGGGTTGCATGTAGGCAGGT TGCCCTGTGTTGGCTGCAGGGAGAGACACACTGGTCACTGGAGACCAGTGCACATTGTTGGATT TGATCTTGCTTGGTCTTTTCTCAGTAAGTGAAGCATTGCTCCCTCCAGTGCTTGACTGCATTGT GTTTTCCTTGGTGACTCCAACACCAAGGTACAATGGGCAGTGTTTGGATCCTTCCCTGGAATCA GTGACGAATGCATGGTGTTCTGCCCAATGAGAATGAACCATTTGAACAAATCAAGTAACCTCAA AGGTGTAATTCTCTTGGCATCGTTAATGATTATTGGTAGGAGTAAATAAGTGCAATTCTTTTGT TGTTCTTTTTTGGAGATGAGGTGTCTCTGTGTTGCCCAGGCTGGCCTCAAATCCCTGGGCTTAA GCAATCCTCCTGCCTCAGCCTTGAGTAGCTGGGATCACAGACATGTACCACTGTGCCCAGCTAA GAAATGCAATTCTGAGACCTTGGGTTTTTGTGTATATTATAGTTAATGCCCAGCTAAATTCTAA CTTATTTGAAAAGGGATTTGTTAAACATAAGCAACTGACCTTCTTGGACAAGGAAAGCAATATA TTAAAAAAGAGAAAAAAAAAAGAATCTTTGAGTCCCATTGGTGATTCTCAGCTCTTACTGTGGA TCAGAATCACCTGGGGAATATTTAAATGTACTGATTTCTAGGCCCACTAGTACTCAGTGTTCAG GAGATCTTTGGGAGTGAGGCCCAGGCATTGGATATTTTTTTCCCAAGAGGTCCCTGGTGATCCC CACGTGCAGCCAGCATTGAGAACCACAGCCATAAGAGAGTTCTGCTTCTCTTTCCCCAGCCTCC CTTTATCTCCCCTAACAACCTGTTTCATCGTAGAGATTGTTGATCCATGTGATTTTCCTTTTTC TAGATTAAAGATTTCTTGAGCTACCTCTGTCCTGTGAACGCATATCCAAATGTCATTCCAGTTG GCACAACTATGGATAAAGTTGTCGAAATGTGAGTAGTCACTGGTTGTGGGACTTGGTGTCCCCC TTGGTGGCTCTTGGCTAGGACACAAAGGAGAGTTTGCCTGAATGTTTACAAGTCTAGAATCTGT TTGTTTTGGGACATTTCTGAACTGATACTCATTTCCATTTTTTCCTGGAGTGTTTCCTTTAGTT CCACAGTGTGGCAGAAGGTATAGGTAGTGTTGTCAGCTTCTCCTGGGTTGCAACCCAGCTCCGC CACTTACTAACAGTGCAGTGTGAGCTTGGCCAGATCACTTCTCTGAGCTAGTCATTCTGAATCA GCAAAATAGGAATATTGATGCCTACTTGTTGGTCTTCTTAAAAAAGAAAGAGATGATACAGGGA GATAGTGTAAGAAAAGCACCTAGCACCATGCCAAGTAGGTTGTCAAGTGTCTACTGAATGGATA ACTGAAGCCAAAGGAGAGGTGCAATCGTATTCATGGATGTCTTTTACTACAGTATTACCATTTT CTTACCTCTTCTTTGGGTTTCATTTATGCATTCATGAATGATTTTTTTTTTTTTTTTAGACAGG GTCTCACTCTGTCACCCAGGCTGGAGTACAGTGGCATGATCTCGGCTCACTGCAACCTCCACCT CCTGGGTTCAAACGATTCTCCTGCCTCAGCCTCCCGAGTAGCTGTGACTACAGGTGCATGCCAT CATGCCCGGCTAATTTTTGTATTTTTAGTAGAGACAAGGTTTTGCCATGTTGACCAGGATGGTC TCGAACTCCCGAGCTCAAGTGATCCACCTGTCTCAGCCTCCCAAAGTGTTGGGATTACAGGCAT GAGCCACTGCACCCGGCCCATGAATGATTTCTTTAGTGCCAGCCATATGGTGGGAATGGAGCTT GGGTTCCAATTTGCCTAAGACACAGCCTGTCCTAGCAGAGCTCCAGTCTCACGGAGAGGCCGGG TGCAAAGGCAGCACACAAGCTCAATGGGTGCAGAAGGAATGAGGCCCCGTGTCAGGGAATCTGC TTCGCAGACCCCGATGGGGACAGACAGGACCAGGCTTGCAGATGTCGATGGAAAGGAGGATGGA GAATCTCTGGAGAGAGGTCTGGGTTGGAGACACAGAATTGGAGTTGGCAGTGCAGGTGAGAACT AAAACCATGAGAAAAGAAGAAGTCACCAGGAGTGGGAGGAGGGATCATAGAGCTGAGGCCAGAA CCCTGGGCAGCACATTCAAGGTAGAAGTGAAGGAGGAGAAGCTGGGCCAAGATGGAGAGAGTGG CCCAGACAGCGGGATGAGAGCAAAGGGAAGGGTAAGCAGAGGGTGCCCATGGAGTGTCTTG B ATGAGTTCTTTCGAGGGGCAGATGGCCGAGTATCCAACTATCTCCATAGACCGCTTCGATAGGG AGAACCTGAGGGCCCGCGCCTACTTCCTGTCCCACTGCCACAAAGATCACATGAAAGGATTAAG AGCCCCTACCTTGAAAAGAAGGTTGGAGTGCAGCTTGAAGGTTTATCTATACTGTTCACCTGTG ACTAAGGAGTTGTTGTTAACGAGCCCGAAATACAGATTTTGGAAGAAACGAATTATATCTATTG AAATCGAGACTCCTACCCAGATATCTTTAGTGGATGAAGCATCAGGAGAGAAGGAAGAGATTGT TGTGACTCTCTTACCAGCTGGTCACTGTCCGGGATCAGTTATGTTTTTATTTCAGGGCAATAAT GGAACTGTCCTGTACACAGGAGACTTCAGATTGGCGCAAGGAGAAGCTGCTAGAATGGAGCTTC TGCACTCCGGGGGCAGAGTCAAAGACATCCAAAGTGTATATTTGGATACTACGTTCTGTGATCC AAGATTTTACCAAATTCCAAGTCGGGAGGAGTGTTTAAGTGGAGTCTTAGAGCTGGTCCGAAGC TGGATCACTCGGAGCCCGTACCATGTTGTGTGGCTGAACTGCAAAGCGGCTTATGGCTATGAAT ATCTGTTCACCAACCTTAGTGAAGAATTAGGAGTCCAGGTTCATGTGAATAAGCTAGACATGTT TAGGAACATGCCTGAGATCCTTCATCATCTCACAACAGACCGCAACACTCAGATCCATGCATGC CGGCATCCCAAGGCAGAGGAATATTTTCAGTGGAGCAAATTACCCTGTGGAATTACTTCCAGAA ATAGAATTCCACTCCACATAATCAGCATTAAGCCATCCACCATGTGGTTTGGAGAAAGGAGCAG AAAAACAAATGTAATTGTGAGGACTGGAGAGAGTTCATACAGAGCTTGTTTTTCTTTTCACTCC TCCTACAGTGAGATTAAAGATTTCTTGAGCTACCTCTGTCCTGTGAACGCATATCCAAATGTCA TTCCAGTTGGCACAACTATGGATAAAGTTGTCGAAATCTTAAAGCCTTTATGCCGGTCTTCCCA AAGTACGGAGCCAAAGTATAAACCACTGGGAAAACTGAAGAGAGCTAGAACAGTTCACCGAGAC TCAGAGGAGGAAGATGACTATCTCTTTGATGATCCTCTGCCAATACCTTTAAGGCACAAAGTTC CATACCCGGAAACTTTTCACCCTGAGGTATTTTCAATGACTGCAGTATCAGAAAAGCAGCCTGA AAAACTGAGACAAACCCCAGGATGCTGCAGAGCAGAGTGTATGCAGAGCTCTCGTTTCACAAAC TTTGTAGATTGTGAAGAATCCAACAGTGAAAGTGAAGAAGAAGTAGGAATCCCAGCTTCACTGC AAGGAGATCTGGGCTCTGTACTTCACCTGCAAAAGGCTGATGGGGATGTACCCCAGTGGGAAGT ATTCTTTAAAAGAAATGATGAAATCACAGATGAGAGTTTGGAAAACTTCCCTTCCTCCACAGTG GCAGGGGGATCTCAGTCACCAAAGCTTTTCAGTGACTCTGATGGAGAATCAACTCACATCTCCT CCCAGAATTCTTCCCAGTCAACACACATAACAGAACAAGGAAGTCAAGGCTGGGACAGCCAATC TGATACTGTTTTGTTATCTTCCCAAGAGAGAAACAGTGGGGATATTACTTCCTTGGACAAAGCT GACTACAGACCAACAATCAAAGAGAATATTCCTGCCTCTCTCATGGAACAAAATGTAATTTGCC CAAAGGATACTTACTCTGATTTGAAAAGCAGAGATAAAGATGTGACAATAGTTCCTAGTACTGG AGAACCAACTACTCTAAGCAGTGAGACACATATACCCGAGGAAAAAAGTTTGCTAAATCTTAGC ACAAATGCAGATTCCCAGAGCTCTTCTGATTTTGAAGTTCCCTCAACTCCAGAAGCTGAGTTAC CTAAACGAGAGCATTTACAATATTTATATGAGAAGCTGGCAACTGGTGAGAGTATAGCAGTCAA AAAAAGAAAATGCTCACTCTTAGATACCTAA ATGAGCTCCTTCGAGGGCCAGATGGCCGAGTACCCAACGATCTCAATCGACCGGTTCGACAGAG AGAATCTGAGAGCCAGAGCCTATTTCCTGAGCCACTGTCACAAAGACCACATGAAAGGCCTGAG AGCCCCTACCCTGAAAAGGAGACTGGAATGTAGCCTGAAGGTGTACCTGTACTGCAGCCCTGTC ACAAAGGAGCTGCTGCTCACCAGCCCCAAGTACAGATTCTGGAAGAAGAGAATCATCTCCATCG AGATTGAGACACCAACCCAGATCAGCCTCGTGGATGAGGCCTCTGGCGAAAAGGAAGAGATCGT GGTGACCCTGCTGCCCGCTGGCCACTGCCCCGGCTCCGTCATGTTCCTGTTCCAAGGAAACAAC GGCACCGTGCTGTATACAGGCGACTTCAGACTGGCCCAGGGCGAGGCCGCGAGAATGGAACTGC TGCACAGCGGAGGCAGAGTGAAGGACATCCAGTCAGTGTACTTAGACACCACATTCTGCGACCC CAGATTCTACCAGATCCCCAGCCGGGAAGAGTGCCTGTCTGGCGTGCTGGAACTGGTGAGATCT TGGATCACAAGAAGCCCCTACCACGTGGTTTGGCTGAACTGCAAGGCCGCTTACGGCTACGAGT ACCTGTTTACAAACCTGTCTGAAGAGCTTGGAGTGCAGGTGCACGTGAACAAGCTGGACATGTT CCGGAACATGCCTGAGATCCTGCACCACCTGACCACAGATAGAAATACCCAGATTCACGCCTGC CGGCACCCTAAAGCCGAAGAGTACTTCCAGTGGAGCAAGCTTCCATGTGGCATCACATCTCGCA ACAGAATCCCCCTGCATATCATCTCTATCAAGCCTAGCACCATGTGGTTCGGCGAAAGAAGCAG GAAGACCAATGTGATCGTGCGGACCGGAGAAAGCAGCTACAGAGCCTGTTTTAGCTTCCACAGC AGCTACAGCGAAATCAAGGATTTCCTGAGCTATTTGTGTCCTGTGAACGCCTACCCCAACGTGA TCCCAGTTGGCACCACCATGGACAAGGTCGTGGAAATCCTGAAGCCTCTGTGCAGATCCAGCCA GTCTACTGAGCCTAAGTACAAGCCCCTGGGCAAGCTGAAAAGAGCCAGAACCGTGCACAGAGAT AGCGAAGAGGAAGATGATTACCTGTTTGATGACCCTCTGCCTATCCCTCTGCGGCACAAGGTGC CTTACCCTGAGACCTTCCACCCTGAGGTGTTTAGCATGACCGCCGTGTCCGAGAAGCAGCCTGA AAAACTGCGGCAGACCCCAGGCTGCTGCCGGGCTGAGTGCATGCAGTCTTCCCGCTTTACCAAC TTCGTGGACTGCGAGGAGTCTAACAGCGAATCTGAGGAAGAGGTGGGCATCCCCGCCTCCCTGC AGGGCGACCTGGGTTCTGTGCTTCATCTGCAAAAGGCCGATGGCGATGTGCCACAGTGGGAGGT GTTCTTCAAGCGGAACGACGAGATCACCGACGAGAGCCTGGAAAACTTTCCTAGCTCCACCGTG GCCGGCGGAAGCCAGTCTCCTAAGCTGTTCAGCGATAGCGACGGCGAAAGCACCCACATTAGCA GCCAGAACAGCTCTCAGAGCACCCACATCACGGAACAGGGATCCCAAGGCTGGGACTCTCAGAG CGACACAGTGCTGCTGAGCAGCCAGGAGAGAAATAGCGGCGATATCACAAGCCTGGACAAGGCC GACTACCGCCCCACCATCAAGGAAAACATTCCGGCTAGCCTGATGGAACAAAATGTGATCTGCC CTAAGGACACCTACAGCGACCTGAAGAGCCGGGACAAGGACGTGACAATCGTGCCTTCCACTGG CGAGCCCACCACCCTGAGCTCCGAAACACATATCCCTGAGGAGAAGAGCCTGCTAAACCTGAGC ACAAACGCCGACTCTCAGTCCAGCAGCGACTTCGAGGTCCCTAGTACACCTGAGGCCGAGCTGC CTAAAAGGGAGCACCTGCAGTACCTGTACGAGAAGCTGGCTACAGGCGAGTCCATCGCTGTGAA AAAGCGGAAGTGCAGCCTGCTGGACACC D MSSFEGQMAEYPTISIDRFDRENLRARAYFLSHCHKDHMKGLRAPTLKRRLECSLKVYLYCSPV TKELLLTSPKYRFWKKRIISIEIETPTQISLVDEASGEKEEIVVTLLPAGHCPGSVMFLFQGNN GTVLYTGDFRLAQGEAARMELLHSGGRVKDIQSVYLDTTFCDPRFYQIPSREECLSGVLELVRS WITRSPYHVVWLNCKAAYGYEYLFTNLSEELGVQVHVNKLDMFRNMPEILHHLTTDRNTQIHAC RHPKAEEYFQWSKLPCGITSRNRIPLHIISIKPSTMWFGERSRKTNVIVRTGESSYRACFSFHS SYSEIKDFLSYLCPVNAYPNVIPVGTTMDKVVEILKPLCRSSQSTEPKYKPLGKLKRARTVHRD SEEEDDYLFDDPLPIPLRHKVPYPETFHPEVFSMTAVSEKQPEKLRQTPGCCRAECMQSSRFTN FVDCEESNSESEEEVGIPASLQGDLGSVLHLQKADGDVPQWEVFFKRNDEITDESLENFPSSTV AGGSQSPKLFSDSDGESTHISSQNSSQSTHITEQGSQGWDSQSDTVLLSSQERNSGDITSLDKA DYRPTIKENIPASLMEQNVICPKDTYSDLKSRDKDVTIVPSTGEPTTLSSETHIPEEKSLLNLS TNADSQSSSDFEVPSTPEAELPKREHLQYLYEKLATGESIAVKKRKCSLLDT Dominant negative mutant of Artemis. V1 A ATGTCCTCATTTGAAGGGCAGATGGCAGAATACCCCACCATTAGCATTGATAGATTTGATAGGG AAAACCTCAGGGCACGGGCTTATTTCCTGAGCCACTGCCATAAGAACCACATGAAAGGGCTCAG GGCACCTACCCTCAAGAGGAGACTGGAGTGCTCCCTCAAAGTCTACCTGTATTGTTCTCCAGTG ACAAAGGAGCTGCTCCTGACTTCCCCCAAATATCGCTTTTGGAAGAAACGAATCATTTCTATCG AGATTGAAACTCCAACCCAGATCAGTCTGGTGGATGAGGCTTCAGGCGAAAAGGAGGAAATTGT GGTCACCCTCCTGCCAGCAGGACACTGTCCAGGTAGCGTCATGTTCCTGTTTCAGGGCAACAAT GGAACCGTGCTGTACACAGGCGACTTCCGCCTCGCTCAGGGAGAGGCAGCTCGAATGGAACTCC TGCATTCTGGCGGACGGGTCAAGGATATCCAGAGTGTGTATCTGGACACCACATTCTGCGATCC CCGGTTTTACCAGATTCCTAGCCGCGAGGAATGTCTGTCCGGAGTGCTGGAGCTGGTGAGGTCA TGGATCACCAGAAGCCCATATCACGTGGTCTGGCTGAACTGCAAGGCAGCCTACGGGTATGAGT ACCTCTTCACAAATCTGTCCGAGGAACTCGGTGTGCAGGTCCATGTGAACAAACTGGACATGTT TCGCAATATGCCCGAGATCCTCCACCATCTGACTACCGATAGGAACACCCAGATTCACGCTTGC AGACATCCCAAGGCAGAGGAATACTTCCAGTGGAGTAAACTGCCTTGTGGCATCACTTCACGGA ACCGCATTCCCCTCCACATCATTAGCATCAAGCCTTCCACCATGTGGTTTGGCGAGCGATCCAG GAAAACCAATGTCATTGTGCGAACAGGAGAAAGCTCCTATAGGGCCTGCTTCTCTTTTCATTCT AGTTACAGTGAGATCAAGGACTTCCTCTCTTATCTGTGTCCTGTGAACGCTTACCCTAATGTCA TCCCAGTGGGCACAACTATGGATAAGGTGGTCGAGATTCTCAAACCACTGTGTCGGTCAAGCCA GAGCACAGAACCCAAGTACAAACCTCTCGGAAAGCTGAAAAGAGCCCGGACTGTGCACCGAGAC AGCGAGGAAGAGGACGATTATCTGTTTGACGATCCCCTGCCTATCCCACTCAGACACAAGGTGC CCTACCCTGAGACTTTCCATCCC B ATGTCCTCATTTGAAGGGCAGATGGCAGAATACCCCACCATTAGCATTGATAGATTTGATAGGG AAAACCTCAGGGCACGGGCTTATTTCCTGAGCCACTGCCATAAGAACCACATGAAAGGGCTCAG GGCACCTACCCTCAAGAGGAGACTGGAGTGCTCCCTCAAAGTCTACCTGTATTGTTCTCCAGTG ACAAAGGAGCTGCTCCTGACTTCCCCCAAATATCGCTTTTGGAAGAAACGAATCATTTCTATCG AGATTGAAACTCCAACCCAGATCAGTCTGGTGGATGAGGCTTCAGGCGAAAAGGAGGAAATTGT GGTCACCCTCCTGCCAGCAGGACACTGTCCAGGTAGCGTCATGTTCCTGTTTCAGGGCAACAAT GGAACCGTGCTGTACACAGGCGACTTCCGCCTCGCTCAGGGAGAGGCAGCTCGAATGGAACTCC TGCATTCTGGCGGACGGGTCAAGGATATCCAGAGTGTGTATCTGGACACCACATTCTGCGATCC CCGGTTTTACCAGATTCCTAGCCGCGAGGAATGTCTGTCCGGAGTGCTGGAGCTGGTGAGGTCA TGGATCACCAGAAGCCCATATCACGTGGTCTGGCTGAACTGCAAGGCAGCCTACGGGTATGAGT ACCTCTTCACAAATCTGTCCGAGGAACTCGGTGTGCAGGTCCATGTGAACAAACTGGACATGTT TCGCAATATGCCCGAGATCCTCCACCATCTGACTACCGATAGGAACACCCAGATTCACGCTTGC AGACATCCCAAGGCAGAGGAATACTTCCAGTGGAGTAAACTGCCTTGTGGCATCACTTCACGGA ACCGCATTCCCCTCCACATCATTAGCATCAAGCCTTCCACCATGTGGTTTGGCGAGCGATCCAG GAAAACCAATGTCATTGTGCGAACAGGAGAAAGCTCCTATAGGGCCTGCTTCTCTTTTCATTCT AGTTACAGTGAGATCAAGGACTTCCTCTCTTATCTGTGTCCTGTGAACGCTTACCCTAATGTCA TCCCAGTGGGCACAACTATGGATAAGGTGGTCGAGATTCTCAAACCACTGTGTCGGTCAAGCCA GAGCACAGAACCCAAGTACAAACCTCTCGGAAAGCTGAAAAGAGCCCGGACTGTGCACCGAGAC AGCGAGGAAGAGGACGATTATCTGTTTGACGATCCCCTGCCTATCCCACTCAGACACAAGGTGC CCTACCCTGAGACTTTCCATCCC D MSSFEGQMAEYPTISIDRFDRENLRARAYFLSHCHKEHMKGLRAPTLKRRLECSLKVYLYCSPV TKELLLTSPKYRFWKKRIISIEIETPTQISLVDEASGEKEEIVVTLLPAGHCPGSVMFLFQGNN GTVLYTGDFRLAQGEAARMELLHSGGRVKDIQSVYLDTTFCDPRFYQIPSREECLSGVLELVRS WITRSPYHVVWLNCKAAYGYEYLFTNLSEELGVQVHVNKLDMFRNMPEILHHLTTDRNTQIHAC RHPKAEEYFQWSKLPCGITSRNRIPLHIISIKPSTMWFGERSRKTNVIVRTGESSYRACFSFHS SYSEIKDFLSYLCPVNAYPNVIPVGTTMDKVVEILKPLCRSSQSTEPKYKPLGKLKRARTVHRD SEEEDDYLFDDPLPIPLRHKVPYPETFHP Dominant negative mutant of Artemis. V2 A ATGAGCTCCTTCGAGGGCCAGATGGCCGAGTACCCAACGATCTCAATCGACCGGTTCGACAGAG AGAATCTGAGAGCCAGAGCCTATTTCCTGAGCCACTGTCACAAAGAACACATGAAAGGCCTGAG AGCCCCTACCCTGAAAAGGAGACTGGAATGTAGCCTGAAGGTGTACCTGTACTGCAGCCCTGTC ACAAAGGAGCTGCTGCTCACCAGCCCCAAGTACAGATTCTGGAAGAAGAGAATCATCTCCATCG AGATTGAGACACCAACCCAGATCAGCCTCGTGGATGAGGCCTCTGGCGAAAAGGAAGAGATCGT GGTGACCCTGCTGCCCGCTGGCCACTGCCCCGGCTCCGTCATGTTCCTGTTCCAAGGAAACAAC GGCACCGTGCTGTATACAGGCGACTTCAGACTGGCCCAGGGCGAGGCCGCGAGAATGGAACTGC TGCACAGCGGAGGCAGAGTGAAGGACATCCAGTCAGTGTACTTAGACACCACATTCTGCGACCC CAGATTCTACCAGATCCCCAGCCGGGAAGAGTGCCTGTCTGGCGTGCTGGAACTGGTGAGATCT TGGATCACAAGAAGCCCCTACCACGTGGTTTGGCTGAACTGCAAGGCCGCTTACGGCTACGAGT ACCTGTTTACAAACCTGTCTGAAGAGCTTGGAGTGCAGGTGCACGTGAACAAGCTGGACATGTT CCGGAACATGCCTGAGATCCTGCACCACCTGACCACAGATAGAAATACCCAGATTCACGCCTGC CGGCACCCTAAAGCCGAAGAGTACTTCCAGTGGAGCAAGCTTCCATGTGGCATCACATCTCGCA ACAGAATCCCCCTGCATATCATCTCTATCAAGCCTAGCACCATGTGGTTCGGCGAAAGAAGCAG GAAGACCAATGTGATCGTGCGGACCGGAGAAAGCAGCTACAGAGCCTGTTTTAGCTTCCACAGC AGCTACAGCGAAATCAAGGATTTCCTGAGCTATTTGTGTCCTGTGAACGCCTACCCCAACGTGA TCCCAGTTGGCACCACCATGGACAAGGTCGTGGAAATCCTGAAGCCTCTGTGCAGATCCAGCCA GTCTACTGAGCCTAAGTACAAGCCCCTGGGCAAGCTGAAAAGAGCCAGAACCGTGCACAGAGAT AGCGAAGAGGAAGATGATTACCTGTTTGATGACCCTCTGCCTATCCCTCTGCGGCACAAGGTGC CTTACCCTGAGACCTTCCACCCTGAGGTGTTTAGCATGACCGCCGTGTCCGAGAAGCAGCCTGA AAAACTGCGGCAGACCCCAGGCTGCTGCCGGGCTGAGTGCATGCAGTCTTCCCGCTTTACCAAC TTCGTGGACTGCGAGGAGTCTAACAGCGAATCTGAGGAAGAGGTGGGCATCCCCGCCTCCCTGC AGGGCGACCTGGGTTCTGTGCTTCATCTGCAAAAGGCCGATGGCGATGTGCCACAGTGGGAGGT GTTCTTCAAGCGGAACGACGAGATCACCGACGAGAGCCTGGAAAACTTTCCTAGCTCCACCGTG GCCGGCGGAAGCCAGTCTCCTAAGCTGTTCAGCGATAGCGACGGCGAAAGCACCCACATTAGCA GCCAGAACAGCTCTCAGAGCACCCACATCACGGAACAGGGATCCCAAGGCTGGGACTCTCAGAG CGACACAGTGCTGCTGAGCAGCCAGGAGAGAAATAGCGGCGATATCACAAGCCTGGACAAGGCC GACTACCGCCCCACCATCAAGGAAAACATTCCGGCTAGCCTGATGGAACAAAATGTGATCTGCC CTAAGGACACCTACAGCGACCTGAAGAGCCGGGACAAGGACGTGACAATCGTGCCTTCCACTGG CGAGCCCACCACCCTGAGCTCCGAAACACATATCCCTGAGGAGAAGAGCCTGCTAAACCTGAGC ACAAACGCCGACTCTCAGTCCAGCAGCGACTTCGAGGTCCCTAGTACACCTGAGGCCGAGCTGC CTAAAAGGGAGCACCTGCAGTACCTGTACGAGAAGCTGGCTACAGGCGAGTCCATCGCTGTGAA AAAGCGGAAGTGCAGCCTGCTGGACACC B ATGAGCTCCTTCGAGGGCCAGATGGCCGAGTACCCAACGATCTCAATCGACCGGTTCGACAGAG AGAATCTGAGAGCCAGAGCCTATTTCCTGAGCCACTGTCACAAAGAACACATGAAAGGCCTGAG AGCCCCTACCCTGAAAAGGAGACTGGAATGTAGCCTGAAGGTGTACCTGTACTGCAGCCCTGTC ACAAAGGAGCTGCTGCTCACCAGCCCCAAGTACAGATTCTGGAAGAAGAGAATCATCTCCATCG AGATTGAGACACCAACCCAGATCAGCCTCGTGGATGAGGCCTCTGGCGAAAAGGAAGAGATCGT GGTGACCCTGCTGCCCGCTGGCCACTGCCCCGGCTCCGTCATGTTCCTGTTCCAAGGAAACAAC GGCACCGTGCTGTATACAGGCGACTTCAGACTGGCCCAGGGCGAGGCCGCGAGAATGGAACTGC TGCACAGCGGAGGCAGAGTGAAGGACATCCAGTCAGTGTACTTAGACACCACATTCTGCGACCC CAGATTCTACCAGATCCCCAGCCGGGAAGAGTGCCTGTCTGGCGTGCTGGAACTGGTGAGATCT TGGATCACAAGAAGCCCCTACCACGTGGTTTGGCTGAACTGCAAGGCCGCTTACGGCTACGAGT ACCTGTTTACAAACCTGTCTGAAGAGCTTGGAGTGCAGGTGCACGTGAACAAGCTGGACATGTT CCGGAACATGCCTGAGATCCTGCACCACCTGACCACAGATAGAAATACCCAGATTCACGCCTGC CGGCACCCTAAAGCCGAAGAGTACTTCCAGTGGAGCAAGCTTCCATGTGGCATCACATCTCGCA ACAGAATCCCCCTGCATATCATCTCTATCAAGCCTAGCACCATGTGGTTCGGCGAAAGAAGCAG GAAGACCAATGTGATCGTGCGGACCGGAGAAAGCAGCTACAGAGCCTGTTTTAGCTTCCACAGC AGCTACAGCGAAATCAAGGATTTCCTGAGCTATTTGTGTCCTGTGAACGCCTACCCCAACGTGA TCCCAGTTGGCACCACCATGGACAAGGTCGTGGAAATCCTGAAGCCTCTGTGCAGATCCAGCCA GTCTACTGAGCCTAAGTACAAGCCCCTGGGCAAGCTGAAAAGAGCCAGAACCGTGCACAGAGAT AGCGAAGAGGAAGATGATTACCTGTTTGATGACCCTCTGCCTATCCCTCTGCGGCACAAGGTGC CTTACCCTGAGACCTTCCACCCTGAGGTGTTTAGCATGACCGCCGTGTCCGAGAAGCAGCCTGA AAAACTGCGGCAGACCCCAGGCTGCTGCCGGGCTGAGTGCATGCAGTCTTCCCGCTTTACCAAC TTCGTGGACTGCGAGGAGTCTAACAGCGAATCTGAGGAAGAGGTGGGCATCCCCGCCTCCCTGC AGGGCGACCTGGGTTCTGTGCTTCATCTGCAAAAGGCCGATGGCGATGTGCCACAGTGGGAGGT GTTCTTCAAGCGGAACGACGAGATCACCGACGAGAGCCTGGAAAACTTTCCTAGCTCCACCGTG GCCGGCGGAAGCCAGTCTCCTAAGCTGTTCAGCGATAGCGACGGCGAAAGCACCCACATTAGCA GCCAGAACAGCTCTCAGAGCACCCACATCACGGAACAGGGATCCCAAGGCTGGGACTCTCAGAG CGACACAGTGCTGCTGAGCAGCCAGGAGAGAAATAGCGGCGATATCACAAGCCTGGACAAGGCC GACTACCGCCCCACCATCAAGGAAAACATTCCGGCTAGCCTGATGGAACAAAATGTGATCTGCC CTAAGGACACCTACAGCGACCTGAAGAGCCGGGACAAGGACGTGACAATCGTGCCTTCCACTGG CGAGCCCACCACCCTGAGCTCCGAAACACATATCCCTGAGGAGAAGAGCCTGCTAAACCTGAGC ACAAACGCCGACTCTCAGTCCAGCAGCGACTTCGAGGTCCCTAGTACACCTGAGGCCGAGCTGC CTAAAAGGGAGCACCTGCAGTACCTGTACGAGAAGCTGGCTACAGGCGAGTCCATCGCTGTGAA AAAGCGGAAGTGCAGCCTGCTGGACACC D MSSFEGQMAEYPTISIDRFDRENLRARAYFLSHCHKEHMKGLRAPTLKRRLECSLKVYLYCSPV TKELLLTSPKYRFWKKRIISIEIETPTQISLVDEASGEKEEIVVTLLPAGHCPGSVMFLFQGNN GTVLYTGDFRLAQGEAARMELLHSGGRVKDIQSVYLDTTFCDPRFYQIPSREECLSGVLELVRS WITRSPYHVVWLNCKAAYGYEYLFTNLSEELGVQVHVNKLDMFRNMPEILHHLTTDRNTQIHAC RHPKAEEYFQWSKLPCGITSRNRIPLHIISIKPSTMWFGERSRKTNVIVRTGESSYRACFSFHS SYSEIKDFLSYLCPVNAYPNVIPVGTTMDKVVEILKPLCRSSQSTEPKYKPLGKLKRARTVHRD SEEEDDYLFDDPLPIPLRHKVPYPETFHPEVFSMTAVSEKQPEKLRQTPGCCRAECMQSSRFTN FVDCEESNSESEEEVGIPASLQGDLGSVLHLQKADGDVPQWEVFFKRNDEITDESLENFPSSTV AGGSQSPKLFSDSDGESTHISSQNSSQSTHITEQGSQGWDSQSDTVLLSSQERNSGDITSLDKA DYRPTIKENIPASLMEQNVICPKDTYSDLKSRDKDVTIVPSTGEPTTLSSETHIPEEKSLLNLS TNADSQSSSDFEVPSTPEAELPKREHLQYLYEKLATGESIAVKKRKCSLLDT Dominant negative mutant of Artemis. V3 A ATGAGCTCCTGTCACAAAGACCACATGAAAGGCCTGAGAGCCCCTACCCTGAAAAGGAGACTGG AATGTAGCCTGAAGGTGTACCTGTACTGCAGCCCTGTCACAAAGGAGCTGCTGCTCACCAGCCC CAAGTACAGATTCTGGAAGAAGAGAATCATCTCCATCGAGATTGAGACACCAACCCAGATCAGC CTCGTGGATGAGGCCTCTGGCGAAAAGGAAGAGATCGTGGTGACCCTGCTGCCCGCTGGCCACT GCCCCGGCTCCGTCATGTTCCTGTTCCAAGGAAACAACGGCACCGTGCTGTATACAGGCGACTT CAGACTGGCCCAGGGCGAGGCCGCGAGAATGGAACTGCTGCACAGCGGAGGCAGAGTGAAGGAC ATCCAGTCAGTGTACTTAGACACCACATTCTGCGACCCCAGATTCTACCAGATCCCCAGCCGGG AAGAGTGCCTGTCTGGCGTGCTGGAACTGGTGAGATCTTGGATCACAAGAAGCCCCTACCACGT GGTTTGGCTGAACTGCAAGGCCGCTTACGGCTACGAGTACCTGTTTACAAACCTGTCTGAAGAG CTTGGAGTGCAGGTGCACGTGAACAAGCTGGACATGTTCCGGAACATGCCTGAGATCCTGCACC ACCTGACCACAGATAGAAATACCCAGATTCACGCCTGCCGGCACCCTAAAGCCGAAGAGTACTT CCAGTGGAGCAAGCTTCCATGTGGCATCACATCTCGCAACAGAATCCCCCTGCATATCATCTCT ATCAAGCCTAGCACCATGTGGTTCGGCGAAAGAAGCAGGAAGACCAATGTGATCGTGCGGACCG GAGAAAGCAGCTACAGAGCCTGTTTTAGCTTCCACAGCAGCTACAGCGAAATCAAGGATTTCCT GAGCTATTTGTGTCCTGTGAACGCCTACCCCAACGTGATCCCAGTTGGCACCACCATGGACAAG GTCGTGGAAATCCTGAAGCCTCTGTGCAGATCCAGCCAGTCTACTGAGCCTAAGTACAAGCCCC TGGGCAAGCTGAAAAGAGCCAGAACCGTGCACAGAGATAGCGAAGAGGAAGATGATTACCTGTT TGATGACCCTCTGCCTATCCCTCTGCGGCACAAGGTGCCTTACCCTGAGACCTTCCACCCTGAG GTGTTTAGCATGACCGCCGTGTCCGAGAAGCAGCCTGAAAAACTGCGGCAGACCCCAGGCTGCT GCCGGGCTGAGTGCATGCAGTCTTCCCGCTTTACCAACTTCGTGGACTGCGAGGAGTCTAACAG CGAATCTGAGGAAGAGGTGGGCATCCCCGCCTCCCTGCAGGGCGACCTGGGTTCTGTGCTTCAT CTGCAAAAGGCCGATGGCGATGTGCCACAGTGGGAGGTGTTCTTCAAGCGGAACGACGAGATCA CCGACGAGAGCCTGGAAAACTTTCCTAGCTCCACCGTGGCCGGCGGAAGCCAGTCTCCTAAGCT GTTCAGCGATAGCGACGGCGAAAGCACCCACATTAGCAGCCAGAACAGCTCTCAGAGCACCCAC ATCACGGAACAGGGATCCCAAGGCTGGGACTCTCAGAGCGACACAGTGCTGCTGAGCAGCCAGG AGAGAAATAGCGGCGATATCACAAGCCTGGACAAGGCCGACTACCGCCCCACCATCAAGGAAAA CATTCCGGCTAGCCTGATGGAACAAAATGTGATCTGCCCTAAGGACACCTACAGCGACCTGAAG AGCCGGGACAAGGACGTGACAATCGTGCCTTCCACTGGCGAGCCCACCACCCTGAGCTCCGAAA CACATATCCCTGAGGAGAAGAGCCTGCTAAACCTGAGCACAAACGCCGACTCTCAGTCCAGCAG CGACTTCGAGGTCCCTAGTACACCTGAGGCCGAGCTGCCTAAAAGGGAGCACCTGCAGTACCTG TACGAGAAGCTGGCTACAGGCGAGTCCATCGCTGTGAAAAAGCGGAAGTGCAGCCTGCTGGACA CC B ATGAGCTCCTGTCACAAAGACCACATGAAAGGCCTGAGAGCCCCTACCCTGAAAAGGAGACTGG AATGTAGCCTGAAGGTGTACCTGTACTGCAGCCCTGTCACAAAGGAGCTGCTGCTCACCAGCCC CAAGTACAGATTCTGGAAGAAGAGAATCATCTCCATCGAGATTGAGACACCAACCCAGATCAGC CTCGTGGATGAGGCCTCTGGCGAAAAGGAAGAGATCGTGGTGACCCTGCTGCCCGCTGGCCACT GCCCCGGCTCCGTCATGTTCCTGTTCCAAGGAAACAACGGCACCGTGCTGTATACAGGCGACTT CAGACTGGCCCAGGGCGAGGCCGCGAGAATGGAACTGCTGCACAGCGGAGGCAGAGTGAAGGAC ATCCAGTCAGTGTACTTAGACACCACATTCTGCGACCCCAGATTCTACCAGATCCCCAGCCGGG AAGAGTGCCTGTCTGGCGTGCTGGAACTGGTGAGATCTTGGATCACAAGAAGCCCCTACCACGT GGTTTGGCTGAACTGCAAGGCCGCTTACGGCTACGAGTACCTGTTTACAAACCTGTCTGAAGAG CTTGGAGTGCAGGTGCACGTGAACAAGCTGGACATGTTCCGGAACATGCCTGAGATCCTGCACC ACCTGACCACAGATAGAAATACCCAGATTCACGCCTGCCGGCACCCTAAAGCCGAAGAGTACTT CCAGTGGAGCAAGCTTCCATGTGGCATCACATCTCGCAACAGAATCCCCCTGCATATCATCTCT ATCAAGCCTAGCACCATGTGGTTCGGCGAAAGAAGCAGGAAGACCAATGTGATCGTGCGGACCG GAGAAAGCAGCTACAGAGCCTGTTTTAGCTTCCACAGCAGCTACAGCGAAATCAAGGATTTCCT GAGCTATTTGTGTCCTGTGAACGCCTACCCCAACGTGATCCCAGTTGGCACCACCATGGACAAG GTCGTGGAAATCCTGAAGCCTCTGTGCAGATCCAGCCAGTCTACTGAGCCTAAGTACAAGCCCC TGGGCAAGCTGAAAAGAGCCAGAACCGTGCACAGAGATAGCGAAGAGGAAGATGATTACCTGTT TGATGACCCTCTGCCTATCCCTCTGCGGCACAAGGTGCCTTACCCTGAGACCTTCCACCCTGAG GTGTTTAGCATGACCGCCGTGTCCGAGAAGCAGCCTGAAAAACTGCGGCAGACCCCAGGCTGCT GCCGGGCTGAGTGCATGCAGTCTTCCCGCTTTACCAACTTCGTGGACTGCGAGGAGTCTAACAG CGAATCTGAGGAAGAGGTGGGCATCCCCGCCTCCCTGCAGGGCGACCTGGGTTCTGTGCTTCAT CTGCAAAAGGCCGATGGCGATGTGCCACAGTGGGAGGTGTTCTTCAAGCGGAACGACGAGATCA CCGACGAGAGCCTGGAAAACTTTCCTAGCTCCACCGTGGCCGGCGGAAGCCAGTCTCCTAAGCT GTTCAGCGATAGCGACGGCGAAAGCACCCACATTAGCAGCCAGAACAGCTCTCAGAGCACCCAC ATCACGGAACAGGGATCCCAAGGCTGGGACTCTCAGAGCGACACAGTGCTGCTGAGCAGCCAGG AGAGAAATAGCGGCGATATCACAAGCCTGGACAAGGCCGACTACCGCCCCACCATCAAGGAAAA CATTCCGGCTAGCCTGATGGAACAAAATGTGATCTGCCCTAAGGACACCTACAGCGACCTGAAG AGCCGGGACAAGGACGTGACAATCGTGCCTTCCACTGGCGAGCCCACCACCCTGAGCTCCGAAA CACATATCCCTGAGGAGAAGAGCCTGCTAAACCTGAGCACAAACGCCGACTCTCAGTCCAGCAG CGACTTCGAGGTCCCTAGTACACCTGAGGCCGAGCTGCCTAAAAGGGAGCACCTGCAGTACCTG TACGAGAAGCTGGCTACAGGCGAGTCCATCGCTGTGAAAAAGCGGAAGTGCAGCCTGCTGGACA CC D MSSCHKDHMKGLRAPTLKRRLECSLKVYLYCSPVTKELLLTSPKYRFWKKRIISIEIETPTQIS LVDEASGEKEEIVVTLLPAGHCPGSVMFLFQGNNGTVLYTGDFRLAQGEAARMELLHSGGRVKD IQSVYLDTTFCDPRFYQIPSREECLSGVLELVRSWITRSPYHVVWLNCKAAYGYEYLFTNLSEE LGVQVHVNKLDMFRNMPEILHHLTTDRNTQIHACRHPKAEEYFQWSKLPCGITSRNRIPLHIIS IKPSTMWFGERSRKTNVIVRTGESSYRACFSFHSSYSEIKDFLSYLCPVNAYPNVIPVGTTMDK VVEILKPLCRSSQSTEPKYKPLGKLKRARTVHRDSEEEDDYLFDDPLPIPLRHKVPYPETFHPE VFSMTAVSEKQPEKLRQTPGCCRAECMQSSRFTNFVDCEESNSESEEEVGIPASLQGDLGSVLH LQKADGDVPQWEVFFKRNDEITDESLENFPSSTVAGGSQSPKLFSDSDGESTHISSQNSSQSTH ITEQGSQGWDSQSDTVLLSSQERNSGDITSLDKADYRPTIKENIPASLMEQNVICPKDTYSDLK SRDKDVTIVPSTGEPTTLSSETHIPEEKSLLNLSTNADSQSSSDFEVPSTPEAELPKREHLQYL YEKLATGESIAVKKRKCSLLDT Dominant negative mutant of Artemis. V4 A ATGAGCTCCTTCGAGGGCCAGATGGCCGAGTACCCAACGATCTCAATCAACCGGTTCGACAGAG AGAATCTGAGAGCCAGAGCCTATTTCCTGAGCCACTGTCACAAAGACCACATGAAAGGCCTGAG AGCCCCTACCCTGAAAAGGAGACTGGAATGTAGCCTGAAGGTGTACCTGTACTGCAGCCCTGTC ACAAAGGAGCTGCTGCTCACCAGCCCCAAGTACAGATTCTGGAAGAAGAGAATCATCTCCATCG AGATTGAGACACCAACCCAGATCAGCCTCGTGGATGAGGCCTCTGGCGAAAAGGAAGAGATCGT GGTGACCCTGCTGCCCGCTGGCCACTGCCCCGGCTCCGTCATGTTCCTGTTCCAAGGAAACAAC GGCACCGTGCTGTATACAGGCGACTTCAGACTGGCCCAGGGCGAGGCCGCGAGAATGGAACTGC TGCACAGCGGAGGCAGAGTGAAGGACATCCAGTCAGTGTACTTAGACACCACATTCTGCGACCC CAGATTCTACCAGATCCCCAGCCGGGAAGAGTGCCTGTCTGGCGTGCTGGAACTGGTGAGATCT TGGATCACAAGAAGCCCCTACCACGTGGTTTGGCTGAACTGCAAGGCCGCTTACGGCTACGAGT ACCTGTTTACAAACCTGTCTGAAGAGCTTGGAGTGCAGGTGCACGTGAACAAGCTGGACATGTT CCGGAACATGCCTGAGATCCTGCACCACCTGACCACAGATAGAAATACCCAGATTCACGCCTGC CGGCACCCTAAAGCCGAAGAGTACTTCCAGTGGAGCAAGCTTCCATGTGGCATCACATCTCGCA ACAGAATCCCCCTGCATATCATCTCTATCAAGCCTAGCACCATGTGGTTCGGCGAAAGAAGCAG GAAGACCAATGTGATCGTGCGGACCGGAGAAAGCAGCTACAGAGCCTGTTTTAGCTTCCACAGC AGCTACAGCGAAATCAAGGATTTCCTGAGCTATTTGTGTCCTGTGAACGCCTACCCCAACGTGA TCCCAGTTGGCACCACCATGGACAAGGTCGTGGAAATCCTGAAGCCTCTGTGCAGATCCAGCCA GTCTACTGAGCCTAAGTACAAGCCCCTGGGCAAGCTGAAAAGAGCCAGAACCGTGCACAGAGAT AGCGAAGAGGAAGATGATTACCTGTTTGATGACCCTCTGCCTATCCCTCTGCGGCACAAGGTGC CTTACCCTGAGACCTTCCACCCTGAGGTGTTTAGCATGACCGCCGTGTCCGAGAAGCAGCCTGA AAAACTGCGGCAGACCCCAGGCTGCTGCCGGGCTGAGTGCATGCAGTCTTCCCGCTTTACCAAC TTCGTGGACTGCGAGGAGTCTAACAGCGAATCTGAGGAAGAGGTGGGCATCCCCGCCTCCCTGC AGGGCGACCTGGGTTCTGTGCTTCATCTGCAAAAGGCCGATGGCGATGTGCCACAGTGGGAGGT GTTCTTCAAGCGGAACGACGAGATCACCGACGAGAGCCTGGAAAACTTTCCTAGCTCCACCGTG GCCGGCGGAAGCCAGTCTCCTAAGCTGTTCAGCGATAGCGACGGCGAAAGCACCCACATTAGCA GCCAGAACAGCTCTCAGAGCACCCACATCACGGAACAGGGATCCCAAGGCTGGGACTCTCAGAG CGACACAGTGCTGCTGAGCAGCCAGGAGAGAAATAGCGGCGATATCACAAGCCTGGACAAGGCC GACTACCGCCCCACCATCAAGGAAAACATTCCGGCTAGCCTGATGGAACAAAATGTGATCTGCC CTAAGGACACCTACAGCGACCTGAAGAGCCGGGACAAGGACGTGACAATCGTGCCTTCCACTGG CGAGCCCACCACCCTGAGCTCCGAAACACATATCCCTGAGGAGAAGAGCCTGCTAAACCTGAGC ACAAACGCCGACTCTCAGTCCAGCAGCGACTTCGAGGTCCCTAGTACACCTGAGGCCGAGCTGC CTAAAAGGGAGCACCTGCAGTACCTGTACGAGAAGCTGGCTACAGGCGAGTCCATCGCTGTGAA AAAGCGGAAGTGCAGCCTGCTGGACACC B ATGAGCTCCTTCGAGGGCCAGATGGCCGAGTACCCAACGATCTCAATCAACCGGTTCGACAGAG AGAATCTGAGAGCCAGAGCCTATTTCCTGAGCCACTGTCACAAAGACCACATGAAAGGCCTGAG AGCCCCTACCCTGAAAAGGAGACTGGAATGTAGCCTGAAGGTGTACCTGTACTGCAGCCCTGTC ACAAAGGAGCTGCTGCTCACCAGCCCCAAGTACAGATTCTGGAAGAAGAGAATCATCTCCATCG AGATTGAGACACCAACCCAGATCAGCCTCGTGGATGAGGCCTCTGGCGAAAAGGAAGAGATCGT GGTGACCCTGCTGCCCGCTGGCCACTGCCCCGGCTCCGTCATGTTCCTGTTCCAAGGAAACAAC GGCACCGTGCTGTATACAGGCGACTTCAGACTGGCCCAGGGCGAGGCCGCGAGAATGGAACTGC TGCACAGCGGAGGCAGAGTGAAGGACATCCAGTCAGTGTACTTAGACACCACATTCTGCGACCC CAGATTCTACCAGATCCCCAGCCGGGAAGAGTGCCTGTCTGGCGTGCTGGAACTGGTGAGATCT TGGATCACAAGAAGCCCCTACCACGTGGTTTGGCTGAACTGCAAGGCCGCTTACGGCTACGAGT ACCTGTTTACAAACCTGTCTGAAGAGCTTGGAGTGCAGGTGCACGTGAACAAGCTGGACATGTT CCGGAACATGCCTGAGATCCTGCACCACCTGACCACAGATAGAAATACCCAGATTCACGCCTGC CGGCACCCTAAAGCCGAAGAGTACTTCCAGTGGAGCAAGCTTCCATGTGGCATCACATCTCGCA ACAGAATCCCCCTGCATATCATCTCTATCAAGCCTAGCACCATGTGGTTCGGCGAAAGAAGCAG GAAGACCAATGTGATCGTGCGGACCGGAGAAAGCAGCTACAGAGCCTGTTTTAGCTTCCACAGC AGCTACAGCGAAATCAAGGATTTCCTGAGCTATTTGTGTCCTGTGAACGCCTACCCCAACGTGA TCCCAGTTGGCACCACCATGGACAAGGTCGTGGAAATCCTGAAGCCTCTGTGCAGATCCAGCCA GTCTACTGAGCCTAAGTACAAGCCCCTGGGCAAGCTGAAAAGAGCCAGAACCGTGCACAGAGAT AGCGAAGAGGAAGATGATTACCTGTTTGATGACCCTCTGCCTATCCCTCTGCGGCACAAGGTGC CTTACCCTGAGACCTTCCACCCTGAGGTGTTTAGCATGACCGCCGTGTCCGAGAAGCAGCCTGA AAAACTGCGGCAGACCCCAGGCTGCTGCCGGGCTGAGTGCATGCAGTCTTCCCGCTTTACCAAC TTCGTGGACTGCGAGGAGTCTAACAGCGAATCTGAGGAAGAGGTGGGCATCCCCGCCTCCCTGC AGGGCGACCTGGGTTCTGTGCTTCATCTGCAAAAGGCCGATGGCGATGTGCCACAGTGGGAGGT GTTCTTCAAGCGGAACGACGAGATCACCGACGAGAGCCTGGAAAACTTTCCTAGCTCCACCGTG GCCGGCGGAAGCCAGTCTCCTAAGCTGTTCAGCGATAGCGACGGCGAAAGCACCCACATTAGCA GCCAGAACAGCTCTCAGAGCACCCACATCACGGAACAGGGATCCCAAGGCTGGGACTCTCAGAG CGACACAGTGCTGCTGAGCAGCCAGGAGAGAAATAGCGGCGATATCACAAGCCTGGACAAGGCC GACTACCGCCCCACCATCAAGGAAAACATTCCGGCTAGCCTGATGGAACAAAATGTGATCTGCC CTAAGGACACCTACAGCGACCTGAAGAGCCGGGACAAGGACGTGACAATCGTGCCTTCCACTGG CGAGCCCACCACCCTGAGCTCCGAAACACATATCCCTGAGGAGAAGAGCCTGCTAAACCTGAGC ACAAACGCCGACTCTCAGTCCAGCAGCGACTTCGAGGTCCCTAGTACACCTGAGGCCGAGCTGC CTAAAAGGGAGCACCTGCAGTACCTGTACGAGAAGCTGGCTACAGGCGAGTCCATCGCTGTGAA AAAGCGGAAGTGCAGCCTGCTGGACACC D MSSFEGQMAEYPTISINRFDRENLRARAYFLSHCHKDHMKGLRAPTLKRRLECSLKVYLYCSPV TKELLLTSPKYRFWKKRIISIEIETPTQISLVDEASGEKEEIVVTLLPAGHCPGSVMFLFQGNN GTVLYTGDFRLAQGEAARMELLHSGGRVKDIQSVYLDTTFCDPRFYQIPSREECLSGVLELVRS WITRSPYHVVWLNCKAAYGYEYLFTNLSEELGVQVHVNKLDMFRNMPEILHHLTTDRNTQIHAC RHPKAEEYFQWSKLPCGITSRNRIPLHIISIKPSTMWFGERSRKTNVIVRTGESSYRACFSFHS SYSEIKDFLSYLCPVNAYPNVIPVGTTMDKVVEILKPLCRSSQSTEPKYKPLGKLKRARTVHRD SEEEDDYLFDDPLPIPLRHKVPYPETFHPEVFSMTAVSEKQPEKLRQTPGCCRAECMQSSRFTN FVDCEESNSESEEEVGIPASLQGDLGSVLHLQKADGDVPQWEVFFKRNDEITDESLENFPSSTV AGGSQSPKLFSDSDGESTHISSQNSSQSTHITEQGSQGWDSQSDTVLLSSQERNSGDITSLDKA DYRPTIKENIPASLMEQNVICPKDTYSDLKSRDKDVTIVPSTGEPTTLSSETHIPEEKSLLNLS TNADSQSSSDFEVPSTPEAELPKREHLQYLYEKLATGESIAVKKRKCSLLDT Small peptide inhibitor of Artemis A GCACCTAGCCGCAAAAGACGTCAGCGCATGCAGCGC B GCACCTAGCCGCAAAAGACGTCAGCGCATGCAGCGC D APSRKRRQRMQR Full length Xrcc4 protein A ATTGGTTGCAAAACCTTGATCTGTGAAAGCGGGCGTTTTGGAAGATACCGGAAGTAGAGTCACG GAGAGGTAGGATCCGGAAGTGGGGCTGCCTCTTTAAATAACAAAAATCTGAGGTTCTGTTCTTT TTATCTTTTTGCTTTCTTTTTAAAAAAGTTCCCTGCTACTTACCCCTAGAACTCCACAATGCGA GAATCCCCCTCAATTTGTGAGCTCCCGCGACTTCCTCTTGTGGGCTTTTGGGGATGCTAGGGTT CTCGGCATTATCCTCAGGGTGCGACCTGTTCACCCCCTTTTCAGTTTCTCCGTTTGCATCTGAG GGATTCTTGGGAATGCGAAGCACTTTTGAAATGCTCTGTGTTGGTTGTGGGATTGGGAGGACGG TTGAATCCAGAGGGTAGTGTTGAGTAGGCTGTTTGAGCATTTCCCCAGCACTGGCCTGTCCTTT CAATCCCCAGATATTGGTAAACTGTGGGTTCCAACCAGGCATCGAGGCTGAAACGTACTAGGCA ATTTGAGGTCAGGAAAGAACTTTCTGTGGTAACCAATGGGAAGGAACTGCCGTTTGCGGACTGC AGCGATTGATTAGGTACTTTAAAGAGATCAACTGGCAAGACAAATGACAAGGCAACTTTTAATC AGTAGTAGTATTTAGCTTTTTCTGATTTTAATTATCCCATTAGGTGAGGTTCTACTACACACAC ACGTTTTTCTTTCTGCATTTTATCGATGGAGAAACAGGCGCTTTGACATGTTTGAATTTGCGTA GTTCTTGGAATTCTAATAAAGTATTAGAAATGAGAGTTTTTCACTCTTTGCCCCCTTATGGCAA GCTTTTGGTTCTAAATGTGTGGTGTATTTTTTCTCAGGCAGGAGAGAGTTCTTTTCAGAATGTT TTCAATTTTTTATGGACTTAGAAGGTGGATAGAGAGAAAGAGAGAAGGTAACTCACGTGAGATT TTGGTTTATGAACTGTATTCGGCCTATGAGACCCTTTTGTATTTAGGGCAACACAATGATTAGA AGATTTGGGATTCTGCTATTTGTGTTTACATTGTTCACTAGGGCACACAAAGGTTTTGTTTTAA ACTATAACTAACTTGATATTTGAGTCTGTTATATTGAATTGTCAAGAGTTGGTCAAATACACAA ATTAGCAAGTATTTACTGGGTGCCTGCTTTATTCATGGATCTTCAGATTGCAGCATAGGAACAA AGATGGTCTGTTCCTTTAAGGAATTTAATAAGGTTGGGGGAGAGGGGAATAAGAAAGGTATTTA AAAGATACAGTACTCTCCACCTAAGGATAAAAAAAGTCTTTTAATGTTCTGTCTTGTAATTCCT TTATATTATACCTTTTAGGTCTTGCCATTCAAATTAAACAAACCTGGTTTAGTTATGGAAATTA TGTTGTGCAATTTATCGAGCTTGGCTTTTAGGGCAGTAAATGTGTCTGTAGACATAACTGCCCT TGGTTTCATGTGAAGATTGTCTTGATCTTTGTTACATATAAAGGTAATACTTCTGTATGAAGCT CTGCTTCAGGCTACCTGTGAAAAGCATCAGAAAGCTTAACTTGTTAGAGATCACAATTGATTTG CTATATCTATATATTTTAATTAATTTTAGGCTATGACTTCTTATGTACCTGAGCTTCAAAACAG TAAAGAACGGCATTGCCAGTTTTTAAGTTATCTATAGAGAAACACATATGCCAATAAATGAGGC TGAACAAATATGTATAATGTTTATTGCATTTATGTAAAACATCAAAGTTAATCTGACGTGGTGA GTTTTTTTTGGGAGGTGGTAGTTTAGCTCCATTGTCTTACATAAACCCCCTACTTTTTGGTTTT CAGATTATATCACAATTTCTAAAATCTTTCTGGCAGCTTTGCAGTGAATCCTCATTTAAAACCA TCTTGGATCCTTTCCTTACTAGAAATAAAATCTGTCTGTGTTATTCCTTTGTTCAAAAATTATT ATTTATTTTTATTTTTGAGACAGGATCTTGCTCTGTTGCCCAGGGTGGAGTGCAGTGGCACAAT CATGACTCACTGCAGCCTCAACCTCCAGGGCAGAAGCGATCTATCCTCCTCCCTCAGTATCCCC AGTAACCGGGACCATGGTTGCATGCCACCATACTTGGCTAATTTTATTTTATTTTTTGTAGAGA CAGGGCTCACTATGTTGCCTAGGCTGGTCTCAAACTCCTGGGCTCAAGTGATCCTCCCGCCTCG GCCTCCCAAAGTGCTGGGATTACAGGTGTAGGCCACCGCACCACGTCTGGCCTGTTCAAAAAGT ATTATCTCACCTGCATCTGGAAGAATATTTCCAACTTTGGTTTCATGGGTATATTAAAATCGTA TGTAAAAATAGTGGATATTTGTAGTTTTCTGTGGCGCCAGTGCACAGGTGTCCTCAGTGTTATG AGGATTACATGAGTTATTACAAGTAAATCATCTAGGCAAATGTTTGGCATACAGTAAGCACTCA GAAAGTGTTGGCTATTACTGTGCATGGCTTTGTCTTTGCTAAATTAAAAGTCCCTGGAGAGGAG GAATTATAATGGAGGAATGGTTGAATTGCATATATTAGGCACTAAATACAGTAGTCCCTCCTTA TCTGAGGTTTTGATTTCTGCAGTTTCAGTTACCCATGATCAACCACAGTCTGAAAATATTAAGT AGAAAATTCCAGCCGGGTGCGGTGGCTCATGCCTGTAATTCCAGCACTTTGGGAGACCAAGGCG GGCAGATCACTTGAGGTCAGGAGTTTGAGACCAGCCTGGCCAACATGGTGAAACCCCATCTCTA CTAATATACAAAAATTAGCCAGGCGTGGTGGCATGTGCCTGTAGTCCCAGCTAGTCAGGAGGCT GAGGCAGGAGAATCAATTGAACCCGGGAGGTGGAGGCTGCAGTGAGCCGAGATTGTGCCACTGT ACTCCTGCGTGGGCAACAGAGCGAGACTCCATCTCAAAAAAAAAAAAAAAAATTCCAGAAATAA TGCATACATTTTAAATAGCATGCCTTTCTGAGTTGTGATGAAATCTTATTCCATCCTATCCCAT TCAGCCCGGGGCCATGAATCATCTCCTTGTTTAGCGTATCCCTGCTGTATAAGCTTCCTGCCTT TTAGTTGCTTGGTTATCAGATTGATGGAGGTGGTATCACAGTGCGTGTGTTCTAGGAATACTTA TTTTACTTAATTATTGCTTCAAAGCACAAGAGTAACGACGCTGGCAATTTGGTTATGCCAAAGA GTAGCTGTAAAGTGCCTCTTTTAAGCAAAAAAAGGAAAGTTCTCCACTTAATAAGGAAGAAAAG AAATCCTATGTTGATGTTGTTAAGAACTATGGTAAGAACAAATCTATCTGTAAAATTGTGAATA AGCAAAAAGAAATTTATGCTAGTTTTACTGTCACACCTCAAACTGCCAAACTTATAGCCATAGT GCATTATAAAAGCTTAGTTAAGATAAAAAAGGAATTAAATTTGTGGTTAGAAAATGTGAACAGA AGCATGCTCAGATTGAAGGCAGTTGGATTCAGCCTCCTCACGGGGCCTTGGGATATACACCCTT GGATAAGGAGAGGACTGCTATAAAAGGTTTTAGTATTAAGTTGGTATTGCATTTGTATCACCAG ACCACTTTCTCCCCATTTTCTCTTTTTACTTTGTTGCTAGTGTTAATGATAGGGTTGATTTACA TTACCTTTTACATTACCTACCTTTTTTCATTCACTGTTATTCACATATATTGAAAGACAATTGT TCTGCTTTTTTCCTCTTATCCTCAGCTAGCCTCCCTAACCTCAGGTAGAGGTTTTTCATGTTCC AGTGTTTGTCCTTTTTTTCTCCCCCCTTGTTTTTATTCCCTTCCCACATGGCTTTTCAATTCAG ACTGAAATGTACTTGAGGACCAAAGTTAATACAGTTTTATTCTGTTAGGGATTTTTGTTAAATA AGTAGAGTTTCAGCTGCCCTTGTCACACACAAAAAATAAGATAGATGATAGGTGTTAATCTCCT TGACTAAAATAACCATTTTACTATCTGTGTGTATCCTATAATGTCAACTTGTAAACCTCAAATA TACACATTAACATTTTTTAAAAAAAGAAGTTTCACCAAAAAAGACACTTCTATTTAATGTATGT CTTATTTCTTTTACCTTAAGAAATGTTTCTCTTAACCTTTCTCCATTTTCAACCCCATTTGTTT GCTCTTCTCTGCAACAAAAATCCTCTAAAGAGTTTTCTATGCTCCATGTTCCAATTCCTCTTTT TCTACCTCTGCATCTTCATTGGTATATTTAAAAGATATCTTGAACTCAGATGTCCCAGACCGAA CTCCTTTCCTCCCAAACCTTTCCCATTCTTTCTCATCTGAATTGATGGCAACTTTATACAGCCA GTTGCTCAGTTAAATCTTTGGAGTCATCCTTGACTCCTTCCTTTCTCTTGTATTCCAACAAATC TGTTGGCTTTTTCTATGAAATATATCTAGAATTCAACAGTTTTCTACTATTTCTGCTATTAGTA TACTGATCATCTCTTGCTCAGATTTTTGTTATTACCCACTATCATTTCTTGCCTGGATTATAGT AATTGTGTTCTGTTCTCTCTGCTTTTTTCAGTCCTTGCCTCCCTACAGTCTATTCTCATATGTC AGCCAGAGTGATACTTTTAAAATATAAATAAAAAATTGTGTATTTACATGTAAGATTCTAAATG CAATATGTTATGCTAGATTGGATCCTGAAACAGAAAGAGGTTATTAATGGAAAAACTGGTGAAA TCCAAATAAAGTCTATGGTTTAGTTGATAGAAATGTATCAGTGTTGGTTTCCTGGTTTTGATAA ATGCACCGTGGTAGTATAAGATGTTAATATTAGAAGAAATTGGGTGAGGGGTATATGAGAACTT TCTATTATCTTTGTAACCCTTCTGTAAATTCAGAATTATTTCAAAATAATATACAGAAGAATAA AACATTACTTTTTTGCTTAAAAACCTTTCGTGAATCATTTGATTCATAGTAGAAGCTAACAGCC TTACGTTGGCCTACAATAGTCTACATCAGTCTTGTCCAACTTACAGCTCACAGGCTGCCTGTGG CCTATGATGGCTTTGAATGCGGCCCACCACAAATTTGTAAACTTTCTTAAAACATTATGAGATT TTTTTTTTTTTGAGCCCTTTAGGTATCATTAGTGTTAGTGTATTTTATGTGTGGCCCAAGACAA TTCTTCCTCCAGTGTGGCCTAAGGAAGTCAAAAGATTGGACACCTCTGCTCTACATGATCTGGT CTCCCATTACCTCTCTGACTACATGTCTTTGTATTCTCTCTCCCTTTGTTCCAGCCATACTTAC CACCCTGTTTCTTAAGTACACTAGGCCTACTTCTACCACAGGGCCTTTGCACTGACTGCTGCTT CTTTCTAGAATGCTTTTGGATCCATACAGCTATTCCTTCATAGCTTTTACATGTTGTTCAAATG TCACCTTTGCAGTAAAGCATATCCCAACCTCCCTATTTAAATTGAAGCTTTGCAACTTCCATAG CCCCTACCCCTATCTCCTCCACCCTGTTTTATCTCCTCTTTTTACTTCAGCGCTTATCATTATT CTATATATGTATTACATATTTGTTACATGTATTTTTAATTGTGTTCCCCTATTAAAATGTAAAA TCCATGAAGGCAGGCATTTTTATCTGTTTTGTTGTCTTATGCCACATTCTAAAGCATTTGTCTG AGGCATAGAAGTACTCAGTAGGTTTTGTTTGAATGAATGACTGACTTGATTGGGTGTTTGAATC TGTAATTTTTTTTTTTTTTTTTTTGAGATGGAGTCTTGCTCCGTTTCCCAGGCTGGAGTGCAGT GGCACAATCTCTACTCACTACAACCTCTGCCTCCTGGGTTCCAGCAATTCTCTCTTCTCAGCCT CCTGAGTAGCTGGGATTACAGGTGCATGCCACCATGCCCAGCAAATTTTTTGTATTTTTAGTAC AGACGGGGTTTCACCATGTTGGCCAGACTGGTCTCGAACTCCTGACCTCGTGATCCACCCGCCT CAGCCTCCCAAAGTGCTGGGATTACAGGCATGAAGGTGCTGGGATTACAGGCATGAGCCACCGC ATTTGACCATGAACCTGTAATTTTTGATTTGCAGTCTGAAACACTGAATTATTTATCACTTCCA TGTATCATGCTATTTCTTGCCTCCAAGTTTTTACTCATGCAGACTCTTCTATTTGGAATGCCCT TCCTTATCTTTCTTCCTCTACCCCTAAGTTGTTTTCACCTGACCATTTCTCTTTAAAGATTCGT ATAATATTAGATGTAACTCAAGGAAGCCTTCCCTAAAATGTCAGGCCAGGGTAAGTGCTGCTTT TCAGAGGAGCTCCCTTCCTACCTCTGCATTTTACAAACTTATATTATAATTCTGTTTGGGTGTC TCTATTTCAGTAGAGAGTTGCGAATGTGTCTTACTGATCTTTGGGATATCAAATCCTGGTACAT AGGAAGTAATCAGTGAATGTTTTAATGCATTAATGGCATGATCAAGGACACTCAGCTATGAAGC ATAGTTTTGATTCCAACCTGGGTCTTTTGAGTGTAAAATCAATGGCTTATTTGCTATACCTTGT TTCTTAGGAAAAAGATGGCTGTCTTTAAAATAATTGAAAGGTACTGTATCCTTTTGATACAAGT AGGAGGGAGTTAATGCATTGTATAGCCCTGGACAATTTGCTCCTTGTTATTGCGGAAGCTGCCA GCCCTGATGAAAGTGAGTTGTGCCTTTTTCTAAGGCATTGGCTGAAATCATTGATCAGGGTTCA ATTGCAGACAGCAAATTTTTAATGTTGATGAAATTAGGCACTTTTGGGGAGGAAAACATTCTTG AGATTTGTGTTGCCAAAAAGAAGAAATACTTGCCAAAGAAGAAATACATGCCAAAATTCCAAAC TGTTCATGAGGCATTTATGTTTTTGCTAGATGCCATTACTACCAGTAACTTCATGTTACATTAA ACTTGTGTACCATTGGGAAATCCCAGAGTGTTTAAAGATGTTGCAAAGATTTTCTTTCAGCAGT ACCGAAATTTGCTCTTAAGATTGATTTAATTATGATTAGTTTGTTAACAGTATCTCTGACACGT AGCACAAAATTAGGTAAACTAATTTTGCGTTTAAAATACTGTTTGTTTAATCCTAGATAATGAG CTAGACTTCCCAACTACTCTTTATGATTGGCATCCTGAGTTCAAACTGCCTTCTGAATATTATC ATTATTGTCGCAGCCTATAAACTAAAGCAGTTTTATCTTCACCTAGCCCTTAAGACTAACAAAA AAGGAAATCGATTAGCTCTATAGATTCTGAAAAGGCTTCCACATTAGTAATGTCGTTGCAAATG ATAATTAGGCTTGAGATTAAGTAATCAAAAACAAATATTACCTGGAGGACATTGTATCCTGAAT TTGTGTTCATTTCCATAGCTTTGCTAATCCTACAGAAGTGACTAAAATGTTGAAGTAAGCAAAG AGTTCAATCTGGTCTTGTGTGAGAGAATGCTATTAACTTACTTCTAATTTTACCTGAGCAGTGA ATGAGAATTTTATTGGATAAAGAAGGAACTTGCTCATTTGAAACAGAAGCACATGGCTGCTAAG AAATGAGATGCAGCCATTGTTGAAACCTGTCAAAGTCTTGACAGTATAAATATTGACATGCTGA GACATGTCAATATTTACCATAGAATTTGGAAGTTGCCAAGTTCCTGTTTAAGAAATGTGACCCT AGCATTGGACACAGTATATCAATAAATACGGAACATGTCCAAATGAACAGCTGCTCAGGGAAAA TAAAATTACATCTGTCTAAACGTTGGGGCACTTAAAAAGTTAAAGTTTAAATGTTTATGATTTT TTTTGTAATTTTTAGGTAGATGCTTGTATGATATAGTATACTAATAGAGTTCCATGTATGGGTT TAACATAAAATGACAGTATCATTGCTATTTATAAATTTGTAAATTAGCTGTGCTGTGATACTCA TCTATAAATTGAATTTTAAAAACTTGCCAAGTGTTGTGTTTAGGAACTAACCCTTCATTTTCAA CATTGTTCTTAAGGAGAAATTGGCTCATGATGACTTAGATATTAATTTGGGGAGACAAAAGTTT ATACTCTGATAACTTCTTAAATGGCAACATAGAAAATAGAAGTTTTTGCACTTTAGATGTGATA AGGGAATATGACCTTGTTGTCATTATCTGACAAGCATGTCTCAGTAGAAAATCATATTATAGAT CACCACTGTTAATTCCCATCTGAATATCACTGTATTTTAACAAAAAGCTTTTTGATGCAAAGTA GACATTTGAGCTTTTATATCAAGTCATTAGAACCACACAATCTTACATTGTTTTGCGGACTTCT AGAAGAAGTTTAAACTTAGCAATTCTTTGAACGACAGTCCTAAAACAATCTTAAGAACATAAAA CATGGGTATCAGGACTTGTTTTCTCATTGCTTCTCCTTTCTAATGGTAGTGATAGGTGGCTTTT AAATAGTAATCTAATCATTTAACCAGTTCATAATATTGTATGAGTTCTTAGAAGAAATGAATGA TTTATTAAGTCCATATAGTAGCGTACATTGTAATTAGCTATAGAGTTGACCCTTGAACAATATA GGGGTTAGGGATGCCAACCTCTCACGCAGTTGAAAATCCATGTATAACTTTTGGCTCCTTCAAA ACTTAACTACTAATAGTTTATTGTTGACCAGAAGCCTCATCAATAACATAAACAGTTGATTAAC ATATGTTTTGTGTGTTATATGCATTATGTACTGTATTCTTACAATAAAGTAAGCTAGAAAAAAG TAAATGTTATTAAGAAAATCATAATGAAAGGAAAATATATTTACTATTCATTAAGTGGAAGTCG ATCATCATAAAGGTCTTCATTCTTGTCTTCATGTTGAGCTGGCTGGGGCGGAAGAGGAAGAGAA GGATTGATCTTGCTGTCTCTGGGCTGGCAGAGGTGGCAGAGGTGGCAGAGGTAGAGGAGGTGGA AGAGGAGGCAGGAGAGGTGGACACAGTTGGTGTAACTTTTATTGAGAAACTTTAGAGTGTAAGT GGACCCACACAGAACAAACCTTCAGTTGTTCAGCGATCAACTGTGTATGTGCCTTAATTTAATT TCTCAGTTTTTATCTAGTTTTTTTTTTCAAAAACAGTTTTCTAAGACATTGGCTGGTTCTCTCT CTTTCTCATTTTGTCCTGAGTCAAAGAAATCCCTTAGATATTAAATCAGACATACCTGAACTGA ATGTTCGTACCTAAATGCCTAACCATGATCTTTATGTTCTTGAATGTTCTAATTTGGTTGAATT TTTTTGGCCATCAGCTAAATAGATATCTCTGTTTTATATAACCTCTAAACAAGGTTTAATTAAA AAATCAGGCATTTCTAGGCCAGGAGTGGTGGCTCACACCTGTAATTCCAGCACTTTGGGAGGCC AAAGCAGGTGGATCACCAGAGGTCAGAATTTCAAGTCCAGCCTGGCCAACCTGGTGAAACCCCA TCTCTACCAAAAATACAAAAATTAGCCGGGAGTGGTGGTGCATGCCTGTAATCTCAGCTACTCG GGAGGCTGAGACATGAGAATTGCTTGAACCTGGGAGGCAGAGGTTGCAGTGAGCTGAGATTGCG CCACTGCACTCCAGCCTGGGCAACAGAGTGAGACCCTGTCTCCAAAAAAATAAAAAATAAAAAG ACATTTCTAAATAACAACAGCCCTATAAAATTTGTCCTGGTTGGCTGAGCACAGTGGCTCACAC TTGTAATCCCAGCACTTTGGGAGGCCGAGGCAGGTAGATCATTTGAGGTCAGGCGTTTGAGACC AGCATGGCCAACATAGTGAAACCCCATCTCTACTAAAAATACAAAAATCAGCCAGGCGTGGTGG TGCATGCCTGTAATCCCAGCTACTCAGTAGGCTGAGGCAGGGGAATCACTTGAGCCTGAGAGGT AGAGGTTGCAGTGAGCCGAGATGGTGCCACTGTACTCCAGTCTGGGTGACAGAGTGAGACCCTG TGTCAAAAAAAAAAAATTTTTTTTTTCCTGGTCATAGCGTGTTCATTGTTTCAGCAAGCAAGAT GTCATACTAAAATACACAAAAAAATTAATACAATCTTATCTTTGAAAATTTAGTAATTTACTCT TTTTTTGGTGTATGTCTCTTCTTTATTTGGTTTGGAGCTACATGCCTTGTTAAAATGAAAAGCA TGTACCTCATTTTTCTGGATATTTTGTATTTCTGATGTTTCACTGGGCAGTCTTGTACCTTGGC CAAAGTGGAATATTTATGCAGGCAGAATTGAATTTAATAATATACATTTCAATTGTTAAGGAAA AATAATTTTCAAGGCATTGGAATTGTATTGTCGTTGCTACTGGTGAATCTACTAGTTGATTGTT GGTATTTCATTTTCTGAACATTGGATTCCTCAGGCAAACCTTCTCTTATACCTCTTATTTTTGT TTATATTGGTCCTGTAATTTTTTTACCTTAGAAAATGCAGCATCTTTTTATGTCATTTAGCAGG TATTTGATGTATCTTGTCATTATTTTATTACTACTTTAACTCTGCTGTAGCAAAATTCTATACT ACCTTGTATATATTTACTTATTTTTTAAATAACTAACAAGTTTAATTATAATTTATATAGAACT CTGTATTGTCATGTTCTCCTAAGTGGATGAAAAGTTTCTGGAGAGAAAGTGTCATTACTTTTTT TTTCTGATCTGCTAGAGTTCTCATTGAACACAAAGTTTGCACATACTGCTTCCTTAATGAATGA CTGGTAGATGGAGTGGAATTTTTACAACTGACGTTCTGCAGGTTGATTTCAGTTCGTTATTTCA ACTTAATGGGAAATTTTTAAAACATATTAAGTGACTATGAAACTAACTTGACTGAATAGCTTTT CAGATCAGCATTTTAAATTTTGCTGTGCAGAATTGCTTCTCTTGCACAAAGTAGTGTGGCTTCA TTTGTTAATAAACATTTCATTAATTCTTTTGGGGAAGTGTTTGATTAAAAATAAATTTTTTTTT CTAAGACATGTAACATTCCCAGCTTCTCCCTAATAAGAAAATTATTCATGATAGTTCTGTAGTT TGAAGATTGTTGATGCATATAACATTTCCAACTTCCTTCTAATAAGATAATCATTCTTGATTGT TCTGAAGTTTAAAGATTATTGATAATTTGACTTCATTTTCACTTCATTGTACTTTATAGGCAGG AACATGTTTGATTTAGTGCTATTTCAGAATCCTTTGAAGAAGTCTGACAATCTTTTTAGGATTT TGTTTCAAAATTGATATTAAGTTGTAGCCATAAAGAGGCCACCAATTGATTAATCTTTCTGATC AATAAGGTAATTTAAAGATACTCTTTTAGCTGTGTGACCTTGTTTCACTGCTGCCTGCTGGAGG TGGTTGCCAATTTTGCAGGTAACTAAGTGCTATCAGACACTACCCTTGTAGAAGCACAGCCTCC TAAATTGTGATACCTTGATAACAAATGACTTCTAATCTGGATTAATTTTGTTGCTTGCTTCATT CAAATGTTGGAGAGGCCAGCACATGGGAATCTAACAGAATAGTACTAGAATTCTGAAACTATCA AAGTTCCATTTCTATCAGCCACTAGGTGAGCTTTCTGCTGAGTGATTCAGTGTATGTAATTCAG CTCCAGGCCCTTTCCATCAGGAGAAGAACTGGCAGAGAATCTGCTAAGCATGATTATCCCAATA TCCTTCCTATATTAAACCCTCTTTTTTTCCCCCAGTGGGGGAATAAGATAATTGACTTGGGATC CTTGGAGGCCAATCATAACTCCAATTCTCTAACACCAAGTGGGTATTCAACAATTCAGTACAAT TCAAACACCATCTATCTAGGGTTAGTGTCAGATCCCACAGGTTTGTGGGCTCAGTCTCACAAAA TTGCCTCCACTTCAGATGCCAGTCACAAGTCCTGAGTCACCTATACTTTTGACCAACCAGTTAT AAATCAAGGTTTCCCTTGATTTATGCCTCACGAATAATTTTCTTATTAGGGAGAAGCTGGGAAT GTTACATGTCTTAGAAAAAAAAATTATTTTTAATCAAACACTTCCCCAAAAGAATTAATGAAAT GTTTATTAACAAATGAAGCCACACTACTTTGTGCAAGAGAAGCAATTCTGCCTCAGGTTTGATA ATTTGCTATAATGGGTCACAGAAATCAGAAAAATATTTTATTTACCTTTACTGGTTTAGTACAA AAGATAGAACTTAGGAACAGCCAAATGAGAGAGGACACATAGGGAAAGTTATGGTGGCAGGGGA ACAGGACTTCAATGCCCTTCTGTGGACATGCCACCTTTTAGCACCATGATGTGTTCACCAAGCA GGAAGCTGTTCACATCTCCTTGTTCAAGAGTTTTGTTTTTTTGAGACAGGGTTTCACTCTGTCA CCCAGGTTGGAGTGCAGGTAGCACAATCATAGCTCACTGTAATGTCAAAGGCCTGGGCTCAAGT GATCCTCCTTCCTAAGCCTCCTGATATGGTTTGGCTGTTTCCCCATGTAAATCTGATCTTGAAT TCCCACGTGTTGTGGGAGAGACCCAGTGGGAGGTAATTGAATCATGGGGGCAGTTCTTTTTCAT GCTTTTCTCATGATAGTGAATAAATCTCACGAGATCTGATGGTTTTATAAGGTGGTGGGGTTGG GGGGGGCTCCCTGCACAAGCTCTGTCTCATTGCCTGCTGCCATCCATGTAAGACATGAATTGCT CCTCCATGCCTTCTGCCATGATTATGAGACCGCCTCAGCCATGTGGAACTGTAAGTCCATTAAA CTGTTTTTTTCCATATAAATTACTGAATCTCAGGTATGTCTATCAGCAGTGTGAAAATGGACTT ATAAACCTCCCAATTCAAATTTTTATAGAGCTCAATCTCCTGGTCTGGGTGCATGGGAGGAATG GAGGGTAGGGAGGAGGGTCTGAAAATCCCAGCCTACTAATCACTTGGTGTTTCTGGTGACCAGC TCCATCCTGAGGCTGTCTAGAGGCCCCACTGTAAGTCACTTCATTATTATAAACTCAGGTGTAA TTGAAAGCTGTTCCTTATGAGTAACAAAAACATTCCTATCACTCAGGAAATTTCAAGGGTTTTG CCAACTCTGTGCGAGGAGCAGGGGACAAAGTTCAAACATATTTCTTATAATATCACACACACTC ATTATTTTTTGTTTGTTAAATTTTATTTATATTATATATTATGTTATGGTTGTTTATATTTATG GGGTACAAAGTGATATTATGATTTTGAATGCAATGCAGAATGGTTAAATTAAGCTAATTAACAT ATCTATCCCCTGAAGTATTTAACATTGTTTATTTGTGGCAATATTGAAATGTACAGTACTCAAT TGTTAGCTATGTTCAGCATGCTGTACAATTGATCTAAAATAGAAAAGTCAGACTTATTTCTCAT ATATAACTGAGGCTTTATACTCTTTTGACTGTTGTGTTAGCCTGTTTTCACACTGCTATGAGGA ACTGCCTAAGACTAGGTAAATTATAAGGAAAAGAGGTTTAATTGACCCACAGTTCTGCATGGCT GTGGAGGCCTCAGGAAACTTACAATCATGGCAGAAGGAAAAGCAGGCAGGCATATCTTACATGG TGGCAGGTGAGAGAGAAGAGTGAAATGGGAACTGCCAAACTATTAAAACCATCAGCTCTTGTGA TAACTCACTCCACTATTATGAGAACAGCATGGGGGAAGTCGTCCCTGTGATCCAATCACCTCCC ACCAGGTCCTAGGTCAACATCTGGGGATTACAATTCGAGATGAGATTTGGGTGGGGACACAGCC AAACCATATCAACTGCCCATCCTCCCTACCACCCAGCCTCTGGTAACCACCATTCTACTCTCTG CTTCTGTGAGTTCAATTAATTTAGATTATACATATAAGTGAGAACTGTGGCATTTGTCTTTCTG TGCCTTGCCTATTTCACTTAGGGTAATGTCCTCCAATTCCGTCTGTGATGTCACAAATTACAAA GTTATTTTTATTTTTTAAAGCCTGAATAGTGTTCCATTGTGTGTAGATGAATTTTTTGGTATTC ATTTATCCTCTGATAGACATTTAGGTTTATTCCATTATTTGGCTATTGTCTAGTGCTGCAGTGA ATATGAGACTACAGATGTCTCTTCCACATTCTGATTTTAAAACTTTCAGGTAAATACTCAGAAG TGGGATTGCTGGATCATATAGTAATTCTATTTTTAGTTTTTTGAGGATCCTCCATACTGTTTCC CGTAATGGTTATGCTAATTTATGTTCCTACCAACAGGATACAAAGGTTCCCTTTTTCTCCACCT TCTTGCAAGTGTTTGTTGTTTTTGTTGATAGTGGCCATTCTCACAGATAGGAGGTGATATCTAA TTGTGATTTTAATTTCTATCTCCCTAATGATTAGTGATGGTGAGCGTTTTTTCAAGTATCTATC AGTTATTCAGATGTATTCTTTTGACAAATACCTATTCAGGTCAATAGCTCACGTTTTTATTGGA TTATCTGTTTTGTTTCTATAGAGCTGTTTGATTTCCTCTTATACTTTGGATATTAGCCCTTTAC CAAATATATGGACTGCAGATATTTTCTTAATTCTGTAGGTTGTCTTTTTACTCTGCTAATTGTT TCCTTTGATGTGCAGAAGCTTTCTAGTTTGATGTAATCTCATTTGTCTATCTTTGCTTTTGTTT CCTATGCTTTTAATGTCAAATCCATTTTAATGTCAAATAACAAAAAAGTTATGAAAGCACAGAA CCTAGTGGTATAAGTAATACTGATCAACATTCAGAATATTTTTAGGATGGTAATGGTGGTGTGT AGAGTAATTTTATTCTTAGTACAGGGTTAAAGGACAAAATTATTAATTGCAACCACAGCTACAA TAAACTTTCAAGGGATATATATATTATAATATGATGTAATTTAGACATTAGAAACATAAGATGG CTGGGTAAAGGTGTTGAGTTGTATTTAATCAATGTTAAGCTGCTATCAGGTTAAAATAGACAGA AGTGTAAGATATTCTTTGTAAGCCTCATGGTAGCCAAAAAGCAAAAATCTGTAGGAGATTCACA AAAAATAAAATTAGATTCAAAAGATTCAAGACATACCACACAGGAAACTATCAAACCACAAAGG AAAATTGCAAGAGATGAAGAAGGAAACAAAATATCTTCAAGAAAAAAAGACCCAATGATAGAAA ATAATTAACAAAATGGCGAGAAAGTTAGTCCTTTCCTTACTTATCAACAATTATATTGAGTGTA AACGGATTATATTCTCCTATAAAAGACAAGGAGTAAATGAATGGACACACACACACACACACAC ACACACACAAGACCTAACTACATGCTACCTACAAGGAACTCACTGCACTTTTGAGGACACATAT AGACTGAAAGTGAAGAAATGGAAAAAGATATTCTACACAAATGGTAACCAAAAATCAGCAGAAG TAGCAATACTTACAGCAGAAAATACTTTAAGTCAAAAGCTGTAAAAAGAAGAAAATGAAGGCAT TATATAATGATAAAGTAGTCAGTTTGCCAAGAGGCTATAACAATTATAAATACATATGTACCCA GCAATGGAGCACCTAAATATATAAAGCAAACATTAAAGGGTGTACAGAGATAGACTGTAATACA ATAACAGTAGAGAACTTCAATGCACCACTTTCAATAATGGACAGATAATGTCAGAAAATTAATA AGGCAATGTTAGACTTAAGCAACACTTTAAATGAAATGAACCGTAACAGACATATACAGAGTAT TCCATCTTAACACCAACAGGATACACAATCTTCTCAAATGTACACAGATCATTTCTGGGATAGA TTGTATGTTAGTTCACAAAGCACATCTTAGGAAGTTGAAGAAGACTGAAATCATATCACATATC TTTTCTGACCACAATTGTATGAAACTAGAAATCAATTACGGGAAGAATTTCAGAAAATTCAGAA GTATACTGAAATTAACAACATGCTCCTGAACAACCAATAGGTCAATTGAGGAATTAAAAGGGAA ATTAAAAAATATCTTTAGACAAACAAAAATGAAAACACGGTATGCCAAAATTTATGGGATGTTG TAAAAGTTTTGCTTGTCTGGGAAAGTTTTTATTTCCTTCTTATTTTTGAAAGACATCTTTGCTG GGTAAAGTCTTCTTGGTTGGCAGCATTTTTTTACGCCCCATCCCCCGAGCAGTTTGAATATATC AGCCCACTCTCTCCTGGTCTGGGGTTTCTGCTAAGAAGTTTATTGTTATTTTTATTGGAACCCT TTTATGTGTGATTTCTTTATTATCTTTTGCTGTTTTCAGAATTTTTTCTTTCTCTTTAATTTTT GATAGTTTGATAATTACATGTTATCGTCAACTCCTCTTTGGTTTGAATTTGGTTGGAGATCTCC TTTCTTCATGTACCTGGATGTTGGCTTCCTTCTGATTAGGGAACTTTTCATTTGTTATTTCTTT AAATATGCATCTACCTACTTTGTTTTTCTACTTCTTAATTCCTATTATGTATAGGTTAGGTCTC TTGATGGTGCTCCATAATCCCCATAGGCTCCCCTCCCCTCCTTTCCCGTTCCCTCCCCTTCCCT CCCCTCCCCTCTCCTCCCCTTCCCTCCGCTCCCCTCTCTTCCCCTCCTTTCCCCTCCCCTCTCT TCCCCTCCTCTCCCCTCTTCTCCTCTCCCCTCTCCTCCCCTCTTCTTTCCTTTCCTCTTTTTCT TTTTTTCTTTGCTCCTCTGACTGATTTCAAATGTCCATCTAGAAGCTCACTGATTCTTTCTTCA GCTTCCTCAAGGCAGCTGTTCAAGCTTCCTATTTCATTTTTCAGTTTAGTCGTTGTATTCTTCA TCTCCTGGATATTCATTTTTTAATTGTTTCTATTTCTTTGTCAAACTTTTCATTTTGTTCATGT ATTTTCAAAATTTAATTTTCTATTTATATATTCTTGTGGTTAACTTTTTTTTTTTCCCAAAAGA GTTGAGGTTTCACTCTGTCTCCCAGGCTGGAGACTGGAGTGCAGTGACAAAATCATAGTTCACC ATAGCTTTGAATTCCTGGGCACAAGGGATCCTCCTGCTTCAGCCTCCTGAGTTGCTGGAACTAC AGGTGTGAGCCACCATGTGCTGCCCATTTAACTTTTTAATAAGGATTATTCTGAAATCTTTTTT TTTTTTTTTTTTTACCATTTTATGGATTCCATTTTCTTTGGGATTCATTGTTGGAGTTTTATTC ATTTCTTTTGGAGGTGTCATGATTTCCTGAGTCTTTGTAATCCTGTGTCCTTGTGTTGGTGTTT GCACATTTGTGGAGACAACCACCTTTTCCAGCTTTTACAGGTGTTCGTTGGCAGGGATAGAACT TTACTATTTATTCTAGCCTATACTTCTGGAGGGGCCAGCTAGTAATAACCCTTAGCAGACACAG CTTGCTTTTAGGTTCTGTAGAAAGCTGGCCTGCTACCTTTGCTCTGAATTTTTTTGGGGTAGCT ACATAGGTTCTCTTATCTGACAGGACCACCGTCTGAGCTCTGCAATCAGGCCGAGCTGCTGAAT GGACACAGAAATTTCCTCTGATCAGCCTTGGCCACAGGGTGTATTCCTTTATTTGAGTTCAGCA GTTGGACAGGGTTGCAGGAGGGTCCTTGAGGTTAAGTGGATTGGGGTGGATGGACCAATTTTTA TGTTCAATAGAAATGCTTATTAGAAATGATCAGTGGGGTAGGAAAGTAGGCTTTGAGGCTAGGG ACCACTCTGGTTAAACTCCCTCCTATGTCAGAACAAGTGCCTGCCTGTTGTCAAAATCTGCTGA GGATCTGTTGTGGGATGGTGGAGGCTGGCAAGCCTGTCCCAGTTGCTCAGACTGGCTAGTCTTC TGGTAGTTCTCTACCTAGACAGGATTACTCCTGGACTGCAGCAGAGAGAGGCTGTAGCTAAGCA GAGGCCCTTCAGGATCTGCTGTGGATTGGAGGCTAACAAGTCTGTCCCAGTGCACAGATCATGA ATCTCCTAGCAGATCTTTGTACTTGCAGGATAGTTCTTAAATTGCAGTGAGAGGGGCTGGAGCA GAGACTGGGCCCCTTCACAGTCTGCTGTGGGACAGGAGCTGGCAAGCCTATTCCGGTATTATTA AGATGGATGCTTCTTTCAGCAGTTCCCTGTCCAGGCAAGATAGTTCCCAGCAAGAGGATTGGAG CTGAGACTGAGCCCTTCCAGGATCTGCTGTGGGATGGAGGCAGACACACCCGTTGCAGTGGTTC AGACTTACACGAATCCCAGAAGTTCTTTGCATAGGTGGGATAGTTCCCTTACTGTGGCAGGGAG GGGTTGGAGCTGAGACTGAGCCCTGTCAGGATCTACTGTGGGATGGAGGCTGAGTCACCAAGCC TGCCTTGGTGACTCAGATATATGAGTCTCCCAGCAGTTCTCTACATGGGCAGGATATTTCCAGG GCTGCCGGACAGAAGTGCTGTAGCCAAGAAAGGTCCCCCTTGGGATCTGCTGTGGGATAGAGGG TGGCAATCCCATCCCAGTGGCTCAGATGGGTAAGTGTTTCTCTGGGTTTTTGTGTGACCAGTGA TAAGCGGGAACCACAGATGAGGGGGGCTGGAGCTGAATTATAGGGTAACTTTTGGGTCCACTGC CAAGACTGATGTTGGTGGGCTGACCGGCCTTTGTGGGGCACTTGGGTGTGTAATTCCTCCAGGA CCCCTTGGCAGGTGGTTTTGGTTGCAAAAGCCAAAGGGGGCTGAAGCCAAGCCGTTTGGGGAAC AGGATTATTTCTGTGTTTGAACCCAGGAGCCCAATCTGTGTGTCCAGGTGCAAGTTTGTACCCT CAAAATGGCCTTCCTAAGTCTTGGGCTCCACTTGGGTTTTACAGCCTCCTACCTGAATCCCAAG ACTCCTACAACAAGATTTTTGTTTGTGGATGGCTGCAGAATTCTTATTGTAGGTGTACACATAT AATTTTGGAAACTTTATACCCAGTGTTTTGAAAAACAATATGAGCCAACATTTCAAAGCCAGTT GACTTCTACATAAAAATTGGCATTTGTCAGTTTCTTGAATAATCTGAATGACAGAACACTAAGG ACCAATACTTACCCATAACAATCTGCTTTGCAGTGAGTAATGGCTACCACCTTTATATGGTACT TGTAGTTTCTAGTTTCCCACAGTCCCACTCGTCATGCAATGGATGCATATGACCTCACTCCTGA TCTGCATGGCCCCTGGATATATTAGAACTTGTACCCTTACAAGAGAAAATAGAGCTTGACTTAA ATTTTAGGTATAAATTTTAGTCCATTTTGAGAATGTATAACCCAAGGGTTATACTCAGAACAGA GTCTTGCTTATACTTTGGAACTTCCTCCTGCTGGAGTTGTCCAAAATGTATTCAGAGATGTGGT CAAAAATGACAGACTGAGAAATTGAAGCGTGGGAAATAAATATGTAATTACTCATCCAATTAGG AATGAAAGTGCTTATGTGCTATTTATAACTGTTACTATTATTTGAACTGTATGAAATTGTCATT TTTATAGGTTAAAAATTGTGAAATGTTGGTAATTTTATATAGTTCCTAAATAGTTTTGTATTGC TGAATTTGAGGATATGTTATAGGTTTTGTTTTTTTTTTTTTCCTCAGACTAAGTTGCTCAGTCC TATCACTTGTCATCTTGTTTGCCATTAAGAAATAGGCAGATAAATGGGTGCGGTTTTAAGTAAA TGATGGGTTTGTGAGTGGGGGGAAAAAAGTACATTGTTTATAAGTCTTATTCCTTTTTCACACA AGTGCTTTTAGTTACATTTCAGTTCTGAAAAACACTTTTTTTTTTTAAGTAGAAAAGACTGTAT ATAAGCTTAATTGGTGATGTTTCATAGGAACACCCTCACTCTTTTGGAATTGAAATAAGAGAGG TGTCAAAAATTTTGAGGCTTAAGAAATCATAATTACTGAGTTCTTGTTGAAAAAGACTGCTGCT TAGTTAATGCTGTTTCAGGTACTATCTTATCTCTTCTCTTCAGTTCTGTTAAGTGTCATTCTCA CGTGAAACTGCAATTAGAACTAAAGTGTTCTTGTGACAGTCTAGAAAGTTTCCAAAATGATAAG TGTACTCTCATCCTTTCTGCCAAGTTTATTTGTAATCAAGAGTGGCCGCTCAATGAATATGAAG GAAGTTATAGTCTTGGAACTTAGGGTCCAATTTTAAGAGCACTTTGGAGCTAGGTATTAAATAG TATGTGGGAAATTTGTTCATGCATTAGGTCATTTTATTGCTTTTTAATACCCACTTATAGTGTT AGAGTAGGAAAGGAGAGGAAGTGAAATTTATGTTTATCACTGAAACTAATGATTATTAATGGTA TTTGTAAAAGATAAGCAGAGGAAATGAGAAGTAATATGATATTTGGAATGGCAGCAACTGGCAT TCCACAGTCATGAGAGGTAATTAAGAATGGACTGTGACCTCAACCAAGAGGCCTTATTTTTCTA GACTTATTTTATAGTACTAATGCTCTGTTCCTAAAGCATCAGATTAATTTAATGTCTCCCTTAT ACATCAGCTGTATATTACAAGTTTTTGAATAAGATTATGTTAGCAGTTATAACTGTATTTTACT ACCTTATGGTGACTAAACATTGTGGTTTGCCTGGAATTGAGAGATTTTCTAGGTCTTGGGACTT TGTTTGAAAATTAGGAAAATTCCAGGAATACCTGGACAGGTGGTTACCTTACTTTCAAAATTAT TAAAATGGAGTTAATTCTCACATGATTAGAAGGGTATTTAGTAATCCTGTGAATTCTTTACACT TAATGTTTAGAAAAAAATCTAACTCAAAAATATTATTTTAGGAAAGCACTTTTTATGTAGAAGT GTTGCTGGGTATTTTTGTTTTAATTGCTTTGGAAATTTAAAGGCAAACTGACTTTGTGGTAGTT TTTTCAAAAAAAAAAATCTTAATTTACCCTTTGGTAACACTAACCAGCAAGTTGGCAGGCTATT AATAATGAAAATACTAGCAATAAATTATTCAGTAAAAAAAATCTTTAATGTGGGGAGTGGGTAT TCTGATAAAAAAGGAAAATGCAAATAGTCAGTGCTTTTAAAAAATACTAAACAAGAAATAATCC TTTTCTTTGCACTTAGTTTTCCTAAATTGTTGTGTGATTGTCTCAGAAGTGAATAGCCTAGTGT AGTTTCATAAACCTTTCTTTCCTTTTTTCTAGCAATTATATATGTTCCTGTCTTTGAATTTTTA TAATGTGATAAGACTTTAAAACAATCTGTGACCACACTTTTGGTTTGCAATTTAAATTTTCTCT TTTAAGAATAAAAATAATAAGGTCAAACAAAATAATGTAACCAGGAAACTAATTACAGACTATT AACAGCATATGCTGTGTGCTAATCTTTATTCTGAACTCACTTTAGGTATCAGCCTACTTTTCTC AACAAGGGGGCACTTAAGTTAATTGCTTCATTAGAAACATGCATTTAGCACTTTCTGATCTGTA AGTACAACTCTTTGGCAGAGCTGCAGAAGTTTGAACACCTGCAGCCCAAGCAGCTTAAAAAGAA GTCATAATTTACTATAAAGGAAAATAAAAGAAGCTCAAGTTCAAAATGGTGTTATCAATGATAT AGTGTTGTAACTAACTTGAGCTGACCTAAAAGAGAGAGTTGGCTTCTGCACTGCTCCTTATCAG CATCCAAAAGGGCATACAAAATTCTTTGTAAACTAATTTAAAAAGTGTCTTGTTTATTCAGAAG CAACTGTGAATGGTATTTGTTCAGACCTTAGATCACATCAATTGCATACCAGCCAACAACTTAT TTCTCTTCTAAGAGAGAGGCCAAGTATCAAAGACACAAAGTACTAAAGATAAGCTTCTCAATTC TCAATTGTTCTGAACTCTCAATAAAGCTACTGATGTACAAATTGGGGTGGGACCCAACTGTTTC CACCTGCAGGCTTGTCTTAGATCCTTGGCTCTGGCTGGGAGAGGTGCTGATACTAATGTGACCT TTAGTGCCCTTGGAAAACAAAACACAGGCTTTCTTATAGCCCTAATCAATCAGTCCCTCTGAAG AGGATTCCACCCCGTTTCTTCAAGTAGTCTTGGGGCAAAAAACTATGGCTGACTATTCCCATTT ACAGGGCTGGTGAAAGCAAAGAGATCGTTCATTTGCTCTTACTGAATCTTAAAAGACATTCCAA GTCATCTTTTTTTCTGTTTCCATGGGTGATTCTTACTAGATGTTTTGTATTTGATATTTTGTAA GACGGTGATCTCAGTAAGTAAAAGAATGAAGTGCTTTCAAACCTCATTCAAATAGTATGGTATT AGGAAATTAAGACTTATTTGATATAAAGAACATTTCTGAGACTGCTGAGGCACAAACAAGTTAC TTGTAGGATACTATGTTGTCACTTATGGGCTATTAATGTTAATTGCTTAAATGTGGTTCACAGG TAGTCTCCAAAGGTTCAAATGTGAGTTTACTAAATAATAGAATCTTTAAAATAAAATCATATAA TTTTTGTCATGAGTACCTAGAATTAGAAAATTGGAAAATATTTGAAACATGAATAATTCAAAGA TGTTCTTAAAACTGATCCCCAGATGTCTTTTTAACATCATTGAGATTAAAGCCCTTTATATTAT TGTGAAAGTAGAAGGAGTTACTGAAAGGCATCTGGAATATTGAATTTTAAACAAAATTTTCTCT GTAATTAGAAATTTGTCACTTGGTTCAAATATGGCTTTAAAAAAAAGCAATGAAACCAATTGCT ATTTCACAGTAATTATAAGTGCTGTATTTTCCTTTCACAAAATTATATTAATGGTAACAATAGC CATGGTTCTTAAGGTAAGTTTAAGACAAAATAATCTGTATAAGTATGTGTGCATCTGTGTATGT TTGTATGGAAATACTATAGAGGCAAAAAATGCTATGCCACAAGTAGTTCCTACACCCTCCCATG CACCCCACCCCCAAAATTGTGGGTTTTGAGCCAATTAGAATTATGTAAGCCTTGAACTATATGT CTTTTTCAATGATTGGCATAGAAAAACAGTAACAGATTTTCCAGTAATTTTCAAATTTAAGGAT TACAGAGCATGTGAGTAATTTACTGCACATTAAATGTATTGACTAATTGATCTAAAAGAAAATA TTCACAAATGGATAAAGCATTTCAGAATTAAGCACATCTAGGCAAAGGACCTTATTGTAGGAGA AAATTTTGACTAAATGGAATATTTAAAAATTATTTTTTCTGTGATTATCGTATCAAACCTACAA ACTTAAATATATTTAAAAATTTTACATGCCTAATTGATGGGGCTATAAGGATTACTTTATAATG TTTTTTTAAAGGATCATCTAATGAGAGATTCATGCTATGTGATTAAATAATAGTTGTAATGTTT TCATGTTGGAAGTTTGTGCTTTGTTCCTGATTCTGACTTTTTATAATGTTTTCTCTTTGCATAT TTATAATTTTTATGTTATTTCTCTAGTTTTGTTTATTAGCTTCTACGGTATAAGCATCTTTTAA TGAAGCTCACAAAATCAATTTTACAGTATCAGGCGTTACAGTATTAGAACAAATATAGGTATTT GCTTGAACTAAGTAATATGTGTCATTTTACAGTCTGATAAATTTGAAGTCAATCTGGGCAAGAT TCTAGAGTGATTTACCAGAAGAATTGCTTTTGGATTAAAAGAAAAAGAACCTATCATTGTTACA AATAAGAGTAGGATCACTAATTAACAGTTTTAATTTCTTTTTTTTTTGTTGTTGTTCTTTTAAA TAGTGTTGATAGGCTGGTAGAGTGGATAGATTTTGCCAAGGATTCTTCTTACATTCTTGTGACT TGGAAATATAAGTGGTGTTCCCACATAGTGTTGATGATTGATGTCTACTTGAGGGTGTTTCTAA TGGCAGACTATACAGGTCTATGCCTGAGCTTGTCCTGCTCAACATTTTATGTGCATGACTTGAA TACTTAGAAGAAGAAGTTTATCAGATTTCTAGATGACAAGGTCAGAGAGATAATAAACATGTTG GGTCACAGGAACAGAATCACTATTCAACGTAACCTTAACAAGCCAATATAAAACATAAAATTGA ACCTCAGCAAACACATCAGACAACATCAACAAAAATTACAAACAAAGGATAGAGTAAAAGTGAC TTAGTAATAACATACATAGAAAAACAACTAAACAAGGTTTAGTTGATATTAAACTCAAATAGGA ATTTTTAGAATGATGTAGCTGCCAAAAACATAACAAAATACCCTCAACACAACCCCTATCACTC TCACTATCACTAAAAACAATAATTAAAACTGAATGTGATATTTCCTTGAAATTATAGAAGTGCA GTATTTAGGATGAAGTAATAGTCTTTGTCTATTTTTTAATTGTTTATAATACAACTAGACTACC AGTTGGGACTCAGTGAACTATGCTTTGAGTGGCAGAGATTAACTGTAGAGAATTTTGTGGAGAT TAATCAAACTAGTGAGGGTATCAGAAATCATCTTATAAGAACTGTTTTGACTGCAAGCATATAG TCTTAAGAAGAGGCCTGTCGTGTGTAAGAGGATTTATACTTAATCTGTATGGACCCTACTGGTA TTACTAGGAAAAATGGGTAGAATTCAAGGGTGACAGATCTGAAATAATTTTAAATAAATCCAAG GACAAGTATTTGTGGAAAGCCTTCTTTGGGACAGGCATAGACTTTTCAAATCCTCAGCAGACAT ATCCAGAAGTCAGCAATAGGGCATAGGAGATCAGAGTTGGAAACTTTTTTCTTGTAACTTGTTC CAGAATCAGAACTGGCTGTTTTGTTTCCCACACATCTCATATGATTGCAGAATATAAGCTTGGT TAACTACCATTTGATGGGAGACTGGAAATAAAAGTCTTAGTTTTGTTTTAGAGTAGTCTTAAAA CAACAGCTCCTTATCTGGCAATGCTGTCACATGGCAGAAGCTCCCTAAGCATACCTCTTTCATG GTCCAACCCTGTTTCTTTATCTGGTAACTTTAGAAGTCTGGTTTTTCTTAACATCAGATCTACT AGACTTTCACATTCCTACTGACAAGCAAAGTGCTGTGGTAAGAAGAGCAGGTGGTGGATTTGAG TCCTTGCACCACCACTTAGTGTGTGATCTTGGGTATTAAACTTTACCTCTGTTTTTTATTCATA CAATGAGGATCCTGTTAGTTGCTATATTCATAGGGTTCCAGTAAAGATAGAGCTGATATATATA TATATATATATATGTCAACATATTTCCATTAATTATAGTACTTAATGGATTATTATTTAGTCAC TAAGAATGCTAGGTGTAAAACTCTGTGCCACCATGAAAAAAGCTGTTTATAAGGTTTATTTAAA CATGCGTGTCTGTGGATAAAGACAGAGGGAAATGTTCAGATAATCATTGTTTTGGGAAGGGCAA GATTAGGTTTTTAGAATTTTTATATTATGTGGTTGTCTGTTTGTTCAAGTAATGAAGTTCTTGT GCAGTTGCAAAGTACTTAACAAATGGATGATGGTGATCTTAGATCTGACTCCCTTCTAACTCTA ACTTTCAGTATTACATTGTGTACCCCTAATTTTATTTTCTTCTTTATTGTATGAAGTAAAAAAT TGGCTAACATGAAAACCATGGAAAATGTTTGCAAGAATGTGCAGTAATCAGAATTCTCATACTA TCAATTGTAAACTGGTACAACGCTTTTAGAAAAATATTTGCTGTGTAGCACCAAAATTGAATAT ATCCATATCCTCTGATCCAACAATTTTACTCTTAGGTATATACTCAACAGAAATGCATATGTAT TTGCTAGAGTGTTTCTGCCAGCAGTATTTGTAATAGTCAAAATCTAGAAAGTACCCAGATGCCT ACCACTAGTGGAATGGATAAATAACCTGTCTTATACTCATATAATAGACTACTATACTGCCCTG AAAATCATCTATCACTTTAACACATAGTGTGGATGAATCTTTCAAACATAATGTTGAGCAAAAG AAGCCAGACACAAAATAGAACATGCTGTATGATTATATTTACATAAAGTAGAGAAATATTCAAA GCCCTCATCTCTGTTAGAAGATAAGATAGTGGTTATTTGGAGAGGCCAGTGGCTAGATTGGAGG GAGTGTGAGAATGAATTTTGGGTAGCAATGTTCTGCTTCTTGATCTAGGTACTACTTACATGGA TTTGTTCAACTGTAAAATTCATTGAGTTGTACTTTTGTACTTTTGATGTATGTACTTTTCTGTC TATATATAATACTTAAATACAAAACTTAAAGAATGCAGAAACATTTATTGGCCTCAGGCTGTGA TAATCTGATGCAACTTATCTCTATTACAGAGTGCCCCTGTCTCAGTGGATAGGGTGTTTCAGTC ACTGAGCCTGGTCATCTCTGCCTTAGACAAGGCATGACTGGATACTATCAGCTGTTGGGTTGTG AGATTTTTTTTCCCCCATTGAATTATACTTACTCAACTTTTTCATTCCAGACAGTGTCTCCAGA CAGAGACTAAGATACTTGGTCAATTTTATCCTTTCTAATTACTGTAATATTTCAGTAGTGAGAT CAGTTCCAGGTCATTCTCACAAGTTCTTGCAACCATTTCTTTTGTGGTAGAAAAAAAGCCTATT GAATCTGGGGGAAAAGAAGTGGTAAAATTTACTCAGCATATTGTTGAGATGATAATTTTTTGTT TTTTTTTAGTAGAGACGGGGTTTCACCATGTTGGCCAGACTGGTCTTGAACTCCTGACCTCAGG CAATCTGCCCGTCTTGGCCTCCCAAAGTGCTGGGATTACCGGTGTGAGACACCGCGCCCAGCTG AGATGATAATTTTTATCTTCATTACTTGGACAAATCATTTTCCATTTATGGGCCTCTGCTTTTC TCATCTGTAAAAATTGTGAATTAATATTGAAGAAAACTGTGAATTTACTGAATGTATTATTTAC TGAATTTAATGGTTGAATCTAATGGTTGAACCTATTATACAGTTTTTTTGTTTTGCTTATTTTC TTATTTCCTTGGTGTTTGTGTAGCTGAGAGGCCAGTACAGAAAACATTATTTGAGTTACAGTTT CTTTTAAAAATATTAATTGTATTCTCCCATTACAGGTATTAAGAAATGGAGAGAAAAATAAGCA GAATCCACCTTGTTTCTGAACCCAGTATAACTCATTTTCTACAAGTATCTTGGGAGAAAACACT GGAATCTGGTTTTGTTATTACACTTACTGATGGTCATTCAGCATGGACTGGGACAGGTAATACT AAAAACAAAGTTTTTATAAGTAAAATTTAAGTGTGCTATTCTTCAGTCCTCAGGGATACTTTTC CATTAGATATTGGGTAAAACTGATATTAATTTTACTTGCTATTGCTGTCAAATTTATACACAGG TTTGTAATATTTAATGCCACTTTCTATATTTAATAGTAATAGAAAAACAAACGTGTCCTAGAAA ATTCCGGTTACCATTTGAATCTTAGTAACTTGGATTTGTTCAGAGGTTTAAAATGACCTCTTTA TAGAAAATATAAATAGTACTTTCTAAATACATCTTTTCTCAGGACCCCAGGGAAGAAGTCTGGG GCAGAGGAAGGAGATTGGTTAGGTAAATGGGTATGTGTGTTGCCTTGGGGCAATGGGGTAGTGG TGGGTTATTTATTTATTTATTTTCCCCAGTGAACATATATTACATTTGTAACAAAACAGGACCA GAGTCTAAAAATTTGTAATGCAAGGTTCACACCCACATTTAGGATCTTGGCTGTGATTTTAGGA AATAGATTTTTTTAACTCTTTGGTAATAATATTTTAAAAATGCTAATGACCCTCAAATCATGTA TGGAACATGGTGGATATAAAGTAAAAATATGTAGCCTTATATTTTCCTTATATACGAAGTTTTA ATACTCTTCTAAAGTATCTTATTGAAAGATTTAAAGAACTATTTTTATAATTATGCAAAAGTCT TTTCTAGAGTTATGTTGTGAATAATGTTTTCTGTAAGATAATTTTTACATGTTAATTTACATAC TATTTATATCTTCTATTAACTTTAGAAATATTTCTCTAGAATTTGTTACCATGATTATTATATC GTCTTTAAAATTACAATACATTGTAAAATTTTGTTTCTTTCTTGAGCGTTATGAATTATGTTAT ACAACACAGTCAAATTGAATTTATACTTACAGAGTTTCAAAAAAATTGTCTTTTTTGACACAGA ACAGGTAATGTTGATGTAGGGATTCCTGTAAAATAAAGAATTTTCAGGGGTAATATTTGCAGTA CTTATTATGATATCTATTTAAGCTACACATTTATCTGTAAGAGAAAGCAGAAATCAGATTGGTT GTTGCAGTTCAAGAGTAGAAGATTTGTCAGCTTGGTTTTATGTATGCCAGAGAGATTATATCCA GAAGACAATATTTCTTGTTTTAGGGTGAAGAGTGTATAAGGCTAAAGACAAGGGCAATAGATTA ATGCTGGTCATCTGGGTAAGAAGAGCAGTTCTAACAACACAGCTTGGAAGCAAGTCCTAGGGGA AGTGGTTGCTTGTATGTAAGGAATACTGTATTTATAACTTTAGGTATTTCTAATTGGCAAATGG CGTATTCTGTATACTTAGTTGTTGTCAGACAGATGACCTTAAGGTGTTTCAGGAGCCTTAATTA TCAAAGGAAGAGGCTGAATTCTAATCTAGTCCATAAGCCTCATTCACCAAGATAAAAATCAGTG ATAATATGTTATTTGAAATTTTTTAATCATTAAGTATTGGGGGAAAAAAGAACACTCCATTAAC TCTTATCTCTTAATTTAACCAGAAATGTAAGAACCTTACATTTATGGAACATTTCGTTTATATC ATACAATTGTGCTGGCATCATTCTTAATAATATTAACATGAATTATCATTTCACTAGATGGTAC TGATTTATACTGAGGGTAAGAGACACATTTGGTTTGTCAACACTCTTTGCAATTATCTAGACCG GTACCTACGAAATACATTCTCAATGAATACTTTTTTGATTGAAAGAATGAAAGGATGTCTCAAA TATATAAAACTGGTCTGCGAAAAAAGAAAATAAATTGTTCATTTTAGAGTTAGCATGTTTTTGA ATGAAAACTCCAGTTTTATATTTACTTATTGTTGACATTTGTCATAACTGCAGTATATTCTACC ATTTATTTTTTAGCTAGTGGAATTTAATGTGACAAAAATGTGATATCAAACTTATGTATTCTCA GGTGGATTGTTACCATTTTGGTTTCCTGTACCAAACAAGCTTTAAAACAGAAAATTTTATAGTG CACTATGTGGTCATTTTATTTTCAAAAATATCTAATAGTGTTTAAATCTCTCATGTGTTTTATG CCTTCATTCATTTCTGTTTTCTTGTTTACATATCAGGGACAAAATAGGAAATCAAATAATATAA CACTGTGCCCATGTTTAGTTAAGGCTTATTCCATAAATGTGATCTGGTACTTTACATGTAGACA ATAACATCACTAAGGACATTGAAACAATTAAATAATTGAAACATGGAAACGGATTTCCTTCCGA TACCTCATCCTGTTTTTTTTTGTTCAACATTTTGATTACTGCAACCTTCAATTTGGACAATTTT TTTTCTCTTTTTATTTGAGTGAAATTAAAAGGATGTAAGTTTTCTTTTAATCTCCCCTACACTA AACTCACTGATTTCCATTAGCAATGTTTTATCTAATGAATGTTTTTGAGGTCCAATTATCTAAT TATCATGTGGTCTATCATCACATCAGTATTACAGGCGGTTATATCACAGGGGTAAGTCACAAAG TGGGTTAATGATCGATGACTCTGACTTTCATAAGAATTCCTATTGGCAGTAGGAAACTTATATC ACCCATCTCTGGAGTAGTTTGAAGTTTATTAAAGAGTAAATTAAACTTTACTAATTGTTCTATT ATCCACTAATTAGATCCACTTATAATTATCTTGAGTGTAAATATTTTTTGACTTATATGGAAAT AGTGACAGAACTCAGTGGAAAGAGGATTTTAATAAATCAAGCAGTGAAATGGGTTTATGATGCA ATACCAACTAGAATCCTAATGGTATGATAAGACTGTATGTCTTCTGAGCTCCAGTACAAGCTTA GGATGTGTGCAGGCTTTTGGCTAGTTATATATAGGTATCTGAAGGAAAAAAATCTTCTTTCCTC ACTTACATCTTCATCTACCTATAAACACTGCAAAAGTGATGCTTTTCAGTGTTAAAGTGAGTCT CAGTCTGACTTCTACCAGTTCCTTGTTTTTTGGTCATGTTGGGCTGCTCATGTTTTATGCCTTA TTATGTGGTTCAGTTGCATTCTTGCTGAATTTTATTATTTCCATTGCCTTTATTCTTGGTCACT GAAGTTTTAGAGCATCGCGTGCTTACAGCTATACTTTTTCCAGATGTTCTTGGCACAGAATTCA AAACTGGTGACCAGGTTGGTTTTTTAGGATTGAAGCCCTATGTAGGCAGTCAGATTTCCATGTT TACTTTTATAGGAATTTTTCAAGTACATTTTTGAACAAATAGCTGTTTTACATAATTAATTTCC TTTCATACGTTTTTTTCTCCTTCAAAAATTAAATATTCCGTAATAATCAGCACAGTATTTATTA GGAGAGGAAAATAAGAGGATATCTAGGATGATAACTGACAGATATCTAAAATGTTGTCTAAGAT ATTAGCACTTGAATTTGAGCTCCACAGGCTAGCATTTTTGGAATGAATGAATGATTACATATTT TCAGACAGGTATCTTTTCATTTTAATGAAATTTAGAATACTTTTAACTAGATGCTTTTTAAATA GATGTTCTCTGTTTTCTTTTGTGTTTTCTTCAAGTTTTTCTATGGCCGCATTAAAGATGGCATC TACAAATTTATTTCCTATTTCTCTGTGAAATAACTGTTCTTCCTAGGTATTGGTGAGTTAAAGT TAGATAGTTACTTTTTAACATAATGCAAACACAAAATATGAAATTATTCCTTAAATAGGAAGCA TTTATCTTCTTCTTTTTTTTTTTTTAGAAGAGCTACTAGGGCATTTGAAAGATCAATAGGTTTG ATAGTGATGATCATATTAAATGTGTCCACTTCCAATAGAGAAAATGTGAAAGTGTTTTAGAAGC TGTTAATATATGAATATAAGCTATTTTTATTCTTACCTCCTTCCAAAGGTTGTGTGACGTATGA GAATCATATTTTATTATCAAAACTTGTTATCAAAAATTGATCATATAAAAATATTGGTACCTTG CAAGACTCCCTTTTTCATTAACTGTCATGGGTCTTCCAGACACTTGATAGCATAGAGACCAAAG GTATGAAAATGTGTGTTCCATTTTAGGGATTCTTTAATCATGATTTCCTTATATTCTGTAATAT TTTATACTAATGTTGTTTTTCAAAATTATGGATGGAAATAATTTATCCAATGTTTCATGTCTCT GCTTCACCTCAAAATAAAACATGCAGAGAGATATGAGTATTAATCCCAGCTTCACTAGTTACTT ACTTCATCACCCTAGACCATTACTTGATCTCTGTGAGCCTCAGTTTTCTCTTTTGCAAAATGAA AATAATATCTGTTTTTCAGTTTTATAAGGAATTAAAATAGATAAGTGTAATGCATAAGTATGAA ATTATACAACCATATGAGACTTTTATCATTACTGTGATAGCCTAAATTAACACAGGAAACCATC CAACCACACACACATTCCAACAAATAACGAGATTGAATCTTGTAATTTTAAAAACAAACAAGTA TGCAGACCCATTGCCACTTTTGAGTGTAAGAAAGGGAAAACCTCAGACACCATGTTTGAAGAGG TATTTCAAAACCAAAGTAATTGATGAGAATTAAAGCTTACTTGTAGATTCATGGAATATCTGAA CTAGATATACTTCTAGATGACAGTGAGTATAATGTTTGAGTGAGGTAGAATGTTGAGGCTTCAG ACCTCTTAGGGAATTGGAGTTGAGCTCTCAGCATAAAGAAAGGAACCTGGAAAATATATGCTGT TAATAAAATAATCTTTTAAAAAAACTACTACTCTCTGTCCAGAGGATGCAGCATAAAAACAGAA CAATCCCTAAGGACTATGAGTGAATAAAAGTCTCAAGAAAAATCAGAACCCTAAACCTGTGTTA TGTGTGGATGGGAGGTTTAAAATGGAACACTTTGCCTCAAATGTAAAAATCGAGGTGAGAAATT AACTTTCAAAACTAGTCCCAAACTGATAAAACTTGTAATGACCCCCAGAAAGGCAACCTTCATT TAAGACCACTTCTTCCCAGAGCACTTGCCACTTTGGCTAGAGGTGAGCTGTACTCAAATGTTAC AAAGCATGAAAGGAAAACAAGTAAAACAAGAATTTTTCCACAGATAGAAGAAACATAATTTATA CCCCAGGAGCCACACATAAATACAGAAATGAAAGAGATCTTAAAATACGTTTATTTAAATA B ATGGAGAGAAAAATAAGCAGAATCCACCTTGTTTCTGAACCCAGTATAACTCATTTTCTACAAG TATCTTGGGAGAAAACACTGGAATCTGGTTTTGTTATTACACTTACTGATGGTCATTCAGCATG GACTGGGACAGTTTCTGAATCAGAGATTTCCCAAGAAGCTGATGACATGGCAATGGAAAAAGGG AAATATGTTGGTGAACTGAGAAAAGCATTGTTGTCAGGAGCAGGACCAGCTGATGTATACACGT TTAATTTTTCTAAAGAGTCTTGTTATTTCTTCTTTGAGAAAAACCTGAAAGATGTCTCATTCAG ACTTGGTTCCTTCAACCTAGAGAAAGTTGAAAACCCAGCTGAAGTCATTAGAGAACTTATTTGT TATTGCTTGGACACCATTGCAGAAAATCAAGCCAAAAATGAGCACCTGCAGAAAGAAAATGAAA GGCTTCTGAGAGATTGGAATGATGTTCAAGGACGATTTGAAAAATGTGTGAGTGCTAAGGAAGC TTTGGAGACTGATCTTTATAAGCGGTTTATTCTGGTGTTGAATGAGAAGAAAACAAAAATCAGA AGTTTGCATAATAAATTATTAAATGCAGCTCAAGAACGAGAAAAGGACATCAAACAAGAAGGGG AAACTGCAATCTGTTCTGAAATGACTGCTGACCGAGATCCAGTCTATGATGAGAGTACTGATGA GGAAAGTGAAAACCAAACTGATCTCTCTGGGTTGGCTTCAGCTGCTGTAAGTAAAGATGATTCC ATTATTTCAAGTCTTGATGTCACTGATATTGCACCAAGTAGAAAAAGGAGACAGCGAATGCAAA GAAATCTTGGGACAGAACCTAAAATGGCTCCTCAGGAGAATCAGCTTCAAGAAAAGGAAAAGCC TGATTCTTCACTACCTGAGACGTCTAAAAAGGAGCACATCTCAGCTGAAAACATGTCTTTAGAA ACTCTGAGAAACAGCAGCCCAGAAGACCTCTTTGATGAGATTTAA C ATGGAACGGAAGATCAGCAGAATCCACCTGGTCAGCGAACCCAGCATCACCCACTTCCTGCAGG TGAGCTGGGAGAAGACCCTGGAAAGCGGATTTGTGATCACCCTGACCGACGGCCACAGCGCCTG GACCGGCACAGTGTCCGAGAGCGAGATTTCTCAGGAGGCCGATGACATGGCCATGGAAAAAGGT AAGTACGTGGGCGAGCTGAGAAAGGCCCTGCTGAGCGGCGCCGGCCCCGCCGACGTGTACACCT TCAACTTCAGCAAGGAGAGCTGCTACTTCTTCTTTGAGAAAAACCTGAAGGACGTTTCCTTCAG ACTGGGCAGCTTTAACCTCGAGAAGGTGGAAAATCCTGCCGAAGTGATCCGGGAACTGATCTGT TACTGCCTGGACACCATCGCCGAGAACCAGGCCAAGAACGAACATCTGCAAAAGGAAAACGAGC GGCTGCTGAGAGATTGGAACGACGTGCAGGGCAGATTCGAGAAGTGCGTGTCCGCTAAGGAAGC CCTGGAAACAGATCTTTATAAGCGGTTCATCCTGGTGCTGAATGAGAAAAAGACAAAGATCAGA AGCCTGCACAACAAGCTGCTGAACGCCGCTCAGGAGAGAGAGAAAGATATTAAGCAGGAGGGCG AGACAGCCATCTGTAGCGAGATGACCGCCGACAGAGACCCCGTGTACGACGAGAGCACCGATGA GGAATCTGAGAACCAGACCGACCTGTCTGGACTTGCTTCTGCTGCTGTGTCTAAGGACGACAGC ATCATCAGCAGCCTGGATGTGACCGACATCGCCCCATCTAGAAAAAGAAGACAGCGGATGCAGA GGAACCTGGGCACCGAGCCTAAGATGGCCCCTCAGGAGAATCAACTGCAGGAGAAGGAAAAACC TGATAGCTCTCTGCCTGAGACAAGCAAGAAGGAACACATCAGTGCCGAGAACATGAGCCTGGAA ACACTGCGCAACTCCAGCCCTGAAGATCTGTTCGACGAGATC D MERKISRIHLVSEPSITHFLQVSWEKTLESGFVITLTDGHSAWTGTVSESEISQEADDMAMEKG KYVGELRKALLSGAGPADVYTFNFSKESCYFFFEKNLKDVSFRLGSFNLEKVENPAEVIRELIC YCLDTIAENQAKNEHLQKENERLLRDWNDVQGRFEKCVSAKEALETDLYKRFILVLNEKKTKIR SLHNKLLNAAQEREKDIKQEGETAICSEMTADRDPVYDESTDEESENQTDLSGLASAAVSKDDS IISSLDVTDIAPSRKRRQRMQRNLGTEPKMAPQENQLQEKEKPDSSLPETSKKEHISAENMSLE TLRNSSPEDLFDEI C-terminal domain of Xrcc4 protein A ATGCCTGCCGAAGTGATCCGGGAACTGATCTGTTACTGCCTGGACACCATCGCCGAGAACCAGG CCAAGAACGAACATCTGCAAAAGGAAAACGAGCGGCTGCTGAGAGATTGGAACGACGTGCAGGG CAGATTCGAGAAGTGCGTGTCCGCTAAGGAAGCCCTGGAAACAGATCTTTATAAGCGGTTCATC CTGGTGCTGAATGAGAAAAAGACAAAGATCAGAAGCCTGCACAACAAGCTGCTGAACGCCGCTC AGGAGAGAGAGAAAGATATTAAGCAGGAGGGCGAGACAGCCATCTGTAGCGAGATGACCGCCGA CAGAGACCCCGTGTACGACGAGAGCACCGATGAGGAATCTGAGAACCAGACCGACCTGTCTGGA CTTGCTTCTGCTGCTGTGTCTAAGGACGACAGCATCATCAGCAGCCTGGATGTGACCGACATCG CCCCATCTAGAAAAAGAAGACAGCGGATGCAGAGGAACCTGGGCACCGAGCCTAAGATGGCCCC TCAGGAGAATCAACTGCAGGAGAAGGAAAAACCTGATAGCTCTCTGCCTGAGACAAGCAAGAAG GAACACATCAGTGCCGAGAACATGAGCCTGGAAACACTGCGCAACTCCAGCCCTGAAGATCTGT TCGACGAGATC B ATGCCTGCCGAAGTGATCCGGGAACTGATCTGTTACTGCCTGGACACCATCGCCGAGAACCAGG CCAAGAACGAACATCTGCAAAAGGAAAACGAGCGGCTGCTGAGAGATTGGAACGACGTGCAGGG CAGATTCGAGAAGTGCGTGTCCGCTAAGGAAGCCCTGGAAACAGATCTTTATAAGCGGTTCATC CTGGTGCTGAATGAGAAAAAGACAAAGATCAGAAGCCTGCACAACAAGCTGCTGAACGCCGCTC AGGAGAGAGAGAAAGATATTAAGCAGGAGGGCGAGACAGCCATCTGTAGCGAGATGACCGCCGA CAGAGACCCCGTGTACGACGAGAGCACCGATGAGGAATCTGAGAACCAGACCGACCTGTCTGGA CTTGCTTCTGCTGCTGTGTCTAAGGACGACAGCATCATCAGCAGCCTGGATGTGACCGACATCG CCCCATCTAGAAAAAGAAGACAGCGGATGCAGAGGAACCTGGGCACCGAGCCTAAGATGGCCCC TCAGGAGAATCAACTGCAGGAGAAGGAAAAACCTGATAGCTCTCTGCCTGAGACAAGCAAGAAG GAACACATCAGTGCCGAGAACATGAGCCTGGAAACACTGCGCAACTCCAGCCCTGAAGATCTGT TCGACGAGATC C ATGCCTGCCGAAGTGATCCGGGAACTGATCTGTTACTGCCTGGACACCATCGCCGAGAACCAGG CCAAGAACGAACATCTGCAAAAGGAAAACGAGCGGCTGCTGAGAGATTGGAACGACGTGCAGGG CAGATTCGAGAAGTGCGTGTCCGCTAAGGAAGCCCTGGAAACAGATCTTTATAAGCGGTTCATC CTGGTGCTGAATGAGAAAAAGACAAAGATCAGAAGCCTGCACAACAAGCTGCTGAACGCCGCTC AGGAGAGAGAGAAAGATATTAAGCAGGAGGGCGAGACAGCCATCTGTAGCGAGATGACCGCCGA CAGAGACCCCGTGTACGACGAGAGCACCGATGAGGAATCTGAGAACCAGACCGACCTGTCTGGA CTTGCTTCTGCTGCTGTGTCTAAGGACGACAGCATCATCAGCAGCCTGGATGTGACCGACATCG CCCCATCTAGAAAAAGAAGACAGCGGATGCAGAGGAACCTGGGCACCGAGCCTAAGATGGCCCC TCAGGAGAATCAACTGCAGGAGAAGGAAAAACCTGATA...

Claims

What is Claimed:

1. A modulator or inhibitor of Artemis for promoting sequence integration into a target genomic locus in a cell by non-homologous end joining (NHEJ)-mediated prime editing.

2. The modulator or inhibitor of claim 1 for use in increasing the frequency of integration of a polynucleotide of interest into a target genomic locus in a cell by NHEJ-mediated prime editing.

3. The modulator or inhibitor of claim 1 for use in increasing the integration of a polynucleotide of interest of at least 10 nucleotides in length into a target genomic locus in a cell by NHEJ-mediated prime editing.

4. The modulator or inhibitor of any one of claims 1 to 3, wherein the inhibitor is an Artemis dominant-negative variant or analogue of Artemis.

5. The modulator or inhibitor of claim 4, wherein the dominant-negative variant or analogue of Artemis is a polypeptide that has at least 90 % sequence identity with SEQ ID NO:

14.

6. The modulator or inhibitor of any one of claims 1 to 3, wherein the inhibitor is a β- lactam antibiotic.

7. The modulator or inhibitor of any one of claims 1 to 3, wherein the inhibitor is a from a CRISPR-based gene silencing system.

8. The modulator or inhibitor of any one of claims 1 to 3, wherein the inhibitor is antisense oligonucleotide.

9. The modulator or inhibitor of claim 8, wherein the ASO comprises a sequence selected from SEQ ID NOs: 57-118 or 119-173.

10. The modulator or inhibitor of any one of claims 1 to 3, wherein the inhibitor is a RNAi molecule.

11. The modulator or inhibitor of any one of claims 1 to 10 wherein modulator or inhibitor reduces the expression of Artemis-encoding gene (DCLRE1C) by at least 70%.

12. The modulator or inhibitor of any one of claims 1 to 9, wherein the inhibitor is a polypeptide comprising SEQ ID NO:

20.

13. The modulator or inhibitor of Artemis of any one of claims 1 to 10 for use in increasing the efficiency of gene editing of cells.

14. A method of integrating a polynucleotide of interest into a target genomic locus in aeukaryotic cell, the method comprising: a) contacting a composition comprising the eukaryotic cell with an inhibitor or modulator of Artemis; b) adding a Cas nuclease to the composition; c) adding a reverse transcriptase or a DNA polymerase to the composition; d) adding the polynucleotide of interest to the composition; and d) adding a springRNA; wherein the polynucleotide of interest is inserted into the genome by NHEJ.

15. The method of claim 14, wherein the inhibitor or modulator of Artemis is the inhibitor or modulator as defined according to any one of claims 1-13 16. The method of claim 14 or 15 wherein the Cas nuclease is selected from Cas9, Cas12 or Cas14.

17. The method of claim 14 or 16, wherein the Cas nuclease is a fusion protein comprising a Cas nuclease and a reverse transcriptase or a DNA polymerase.

18. The method of any one of claims 14 to 17, further comprising adding a polynucleotide comprising an RNA guide sequence, a Cas-binding region, and a DNA template sequence, or combinations thereof.

19. The method of any one of claims 14 to 18, wherein the springRNA comprises a primer-binding site, an RNA guide sequence, a Cas-binding region, and a DNA template sequence encoding the polynucleotide of interest.

20. The method of any one of claims 14 to 19, wherein the polynucleotide of interest, the springRNA, and a polynucleotide encoding the Cas fusion protein are encoded on a single vector.

21. The method of claim 20, wherein the vector is a viral vector.

22. The method of claim 20 or 21, wherein the viral vector is a retrovirus, a lentivirus, an adenovirus, or an adeno-associated virus (AAV).

23. The method of any one of claims 14 to 22, wherein the cell is a mammalian cell.

24. The method of any one of claims 14 to 23, wherein the target genomic locus comprises a gene of interest.

25. The method of any one of claims 14 to 24, wherein the Cas protein, the polynucleotide of interest, and springRNA are delivered to the cell by microinjection, electroporation, a lipid nanoparticle, a liposome, an exosome, a gold nanoparticle, or a DNA nanoclew.

26. The method of any one of claims 14 to 25, wherein the polynucleotide of interest comprises a gene of interest.

27. The method of any one of claims 14 to 26, wherein the polynucleotide of interest is 1to 50 base pairs in length.

28. The method of any one of claims 14 to 27, wherein the polynucleotide of interest is double stranded with a 3′ overhang.

29. The method of any one of claims 14 to 28, wherein the polynucleotide of interest is double stranded with a 5′ overhang.

30. The method of any one of claims 14 to 29, wherein the polynucleotide of interest encodes a protein tag.

31. The method of claim 30, wherein the protein tag is selected from a fluorescent tag and an affinity tag.

32. The method of any one of claims 14 to 31, wherein the inhibitor or modulator of Artemis is added to the composition from 0 minutes to about 48 hours before the Cas fusion protein is added to the composition.

33. The method of any one of claims 14 to 32, wherein the inhibitor is added to cells at a concentration of about 1 mM to about 50 mM.

34. The method of any one of claims 14 to 33, wherein the inhibitor or modulator of Artemis is administered at least once, at least twice, or at least three times.

35. A method of gene editing a population of cells comprising: (a) contacting the population of cells with a modulator or inhibitor of Artemis; and (b) introducing NHEJ-mediated prime editing machinery to the population of cells with one or more vectors; thereby editing the genome of the cells.

36. The method of claim 35, wherein the inhibitor or modulator of Artemis is the inhibitor or modulator as defined according to any one of claims 1-13.

37. The method of claim 33 or 36, wherein steps (a) and (b) are carried out ex vivo or in vitro.

38. The method of any one of claims 33 to 37, further comprising enriching the population of cells for cells that have been edited.

39. A population of gene-edited cells prepared according to the method of any one of claims 33 to 38.

40. A pharmaceutical composition comprising the population of gene-edited cells of claim 39.

41. The population of gene-edited cells of claim 39 or the pharmaceutical composition of claim 40 for use in therapy.

42. The population of gene-edited cells according to claim 41, wherein the cells are administered as part of an autologous stem cell transplant procedure or an allogeneicstem cell transplant procedure.

43. A kit for combined, separate, or sequential use, comprising: a) a NHEJ-mediated prime editing machinery; and b) an inhibitor or a modulator of Artemis.

44. An antisense oligonucleotide comprising a oligonucleotide sequences identical to any one of SEQ ID Nos: 57-118 or 119-173.

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