RNA processing protein complexes and uses thereof

Abstract

The invention provides human protein complexes with endonuclease activity. In particular, the invention provides human protein complexes with tRNA splicing endonuclease activity and / or 3' end pre-mRNA endonuclease activity. The invention also provides a splice variant of human Sen2, namely human Sen2deltaEx8, and human protein complexes comprising human Sen2deltaEx8. The human Sen2deltaEx8 complexes have pre-tRNA cleavage activity and / or 3' end pre-mRNA endonuclease activity. The invention also provides human protein complexes with pre-ribosomal RNA cleavage activity. The invention also provides antibodies that immunospecifically bind to a complex described herein or a component thereof, and methods of diagnosing, preventing, treating, managing or ameliorating a disorder utilizing such antibodies. The present invention also provides methods utilizing the complexes described herein, inter alia, in screening, diagnosis, and therapy. The invention further provides methods of preparing and purifying the complexes. The present invention further provides methods of identifying a compound that modulates the expression of a component of a complex described herein, the formation of a complex described herein or the activity of a complex described herein, and methods of preventing, treating, managing or ameliorating a disorder, such as a proliferative disorder, or a symptom thereof utilizing a compound identified in accordance with the methods.

Description

[0001] This application claims the benefit of U.S. Provisional Application Ser. No. 60 / 484,615, filed Jul. 2, 2003, the entire disclosure of which is incorporated by reference herein in its entirety.1. INTRODUCTION[0002] The invention provides human protein complexes with endonuclease activity. In particular, the invention provides human protein complexes with tRNA splicing endonuclease activity and / or 3' end pre-mRNA endonuclease activity. The invention also provides a splice variant of human Sen2, namely human Sen2deltaEx8, and human protein complexes comprising human Sen2deltaEx8. The human Sen2deltaEx8 complexes have RNA-nucleolytic activity. The invention also provides human protein complexes with pre-ribosomal RNA cleavage activity. The invention also provides antibodies that immunospecifically bind to a complex described herein or a component thereof, and methods of diagnosing, preventing, treating, managing or ameliorating a disorder utilizing such antibodies. The present in...

AI Technical Summary

Benefits of technology

[0026] The Sen2deltaEx8 complexes have RNA-nucleolytic activity. In a specific embodiment, Sen2deltaEx8 complexes have pre-tRNA cleavage activity and / or 3' end pre-mRNA endonuclease activity. The invention provides a purified human Sen2deltaEx8 complex comprising: (i) human Sen2deltaEx8 or a functionally active derivative thereof; and (ii) human Sen54 or a functionally active derivative or a functionally active fragment thereof. The invention also provides a human Sen2deltaEx8 complex comprising: (i) human Sen2deltaEx8 or a functionally active derivative thereof; (ii) human Sen54 or a functionally active derivative or a functionally active fragment thereof; (iii) human Sen15 or a functionally active derivative or a functionally active fragment thereof; and (iv) human Sen34 or a functionally active derivative or a functionally active fragment thereof. In a specific embodiment, the complex has RNA-nucleolytic activity. In a specific embodiment, the complex has tRNA endonuclease activity. In a specific embodiment, the complex has 3' end mRNA processing activity. These human Sen2deltaEx8 complexes cleave tRNA at multiple sites and are useful in mapping RNA structure and 3' end pre-mRNA endonuclease processing. In certain embodiments, the fidelity and accuracy of the tRNA cleavage activity of a Sen2deltaEx8 comprising complex is reduced compared to the the tRNA cleavage activity of full length Sen2 comprising complexes.

Problems solved by technology

All of these approaches pose significant drawbacks for the patient.

Surgery, for example, can be contraindicated due to the health of the patient or can be unacceptable to the patient.

Additionally, surgery might not completely remove the neoplastic tissue.

Radiation therapy is effective only when the irradiated neoplastic tissue exhibits a higher sensitivity to radiation than normal tissue, and radiation therapy can also often elicit serious side effects.

However, despite the availability of a variety of chemotherapeutic agents, traditional chemotherapy has many drawbacks (see, for example, Stockdale, 1998, "Principles Of Cancer Patient Management" in Scientific American Medicine, vol.

Almost all chemotherapeutic agents are toxic, and chemotherapy can cause significant, and often dangerous, side effects, including severe nausea, bone marrow depression, immunosuppression, etc.

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