CDK12 Marker for DNA Damage in Transcribed Genomic Loci
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Solution Overview
Problem
Current methods lack a scalable and quantitative assessment of oncogene-induced replicative stress (OI-RS) in tumour cells, which hinders clinical classification and therapeutic development due to the cumbersome and impractical nature of existing assays.
Innovation Solution
CDK12 is used as a marker for DNA damage in proximity to transcribed genomic loci, enabling the identification and quantification of DNA damage events associated with actively transcribed regions through immunofluorescence assays and proximity ligation assays, allowing for the detection of CDK12 recruitment to damaged sites.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Loss of information
If independent evaluation of DNA replication dynamics, transcription evaluation, and DNA damage evaluation is performed, then comprehensive information about oncogene-induced replicative stress is obtained, but the assay becomes cumbersome and impractical for clinical use
Solution Approach 1:
The patent combines three independent evaluation processes (DNA replication dynamics, transcription evaluation, and DNA damage evaluation) into a single integrated assay that detects DNA damage in proximity to transcribed genomic loci using CDK12 as a marker. This merging maintains comprehensive information about oncogene-induced replicative stress while eliminating the cumbersome nature of performing separate assays.
Solution Approach 2:
The assay achieves multi-functionality by simultaneously assessing replication stress, transcriptional activity, and DNA damage response through a single detection system. The method can be applied to various genomic loci and provides universal applicability for evaluating oncogene-induced replicative stress in different clinical contexts.
2Measurement precision
If multiple independent assays are performed to evaluate DNA replication, transcription, and DNA damage, then accurate assessment of replicative stress is achieved, but the method cannot be scaled up for high-productivity analysis
Solution Approach 1:
By merging multiple evaluation processes into a single assay, the patent enables high-throughput analysis while maintaining measurement precision. The combined assay can be performed on large numbers of samples simultaneously, making it suitable for screening campaigns and drug discovery projects that require high productivity.
3Difficulty of detecting and measuring
If existing methods for detecting DNA damage are used, then general DNA breaks can be identified, but DNA damage specifically in proximity to transcribed genomic loci cannot be distinguished
Solution Approach 1:
The patent applies local quality by specifically detecting DNA damage in proximity to transcribed genomic loci rather than detecting all DNA damage uniformly. The use of CDK12 as a marker provides spatial specificity, enabling differentiation between DNA damage occurring in transcribed regions versus other genomic regions.
Solution Approach 2:
The patent uses CDK12 as an intermediary marker to indirectly detect DNA damage in proximity to transcribed genomic loci. Since CDK12 is recruited to DNA damage sites in transcribed regions, it serves as a mediator that provides spatial information about the location and context of DNA damage events.
4Measurement precision
If comprehensive evaluation of genome stability processes is performed, then accurate clinical classification is achieved, but the methods are inherently impractical for clinical application
Solution Approach 1:
The patent merges comprehensive evaluation of genome stability processes into a single practical assay that can be performed in clinical settings. By combining assessment of replication stress, transcriptional activity, and DNA damage into one test, the method maintains classification accuracy while improving ease of operation for clinical application.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach provides a practical and efficient method for identifying DNA breaks in transcribed genomic loci, enabling the assessment of replicative stress and guiding therapeutic protocols, thereby facilitating clinical classification and drug discovery.
Implementation Method 1
proximity ligation assays, allowing for the detection of CDK12 recruitment to damaged sites
Data Source
AI summary
The present invention relates to cyclin-dependent kinase, 12, CDK12 (cyclin-dependent kinase 12), for use as a marker for DNA damage in proximity of transcribed genomic loci in a sample, and to methods for identifying and/or quantifying in a sample DNA damage events associated to actively transcribed genomic loci, comprising detecting the CDK12 protein in proximity of the aforesaid genomic loci.