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Title

Regulation of DNA Repair by Atm and DNA-PKcs during V9D)J Recombination

Date of Award

Spring 5-15-2011

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Immunology)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

V(D)J recombination is the somatic rearrangement process that through which the genetic diversity of antigen receptors is established during lymphocyte development. DNA double strand breaks (DSBs) induced in G1-phase of the cell cycle are necessary intermediates in this process. Accurate and efficient resolution of these lesions is necessary not only for achieving a broad repertoire of antigen recognition specificities, but also for preventing genomic instability that could result in oncogenic transformation events. Atm and DNA-PKcs are ubiquitously expressed proteins that transduce and orchestrate responses to DNA double strand breaks (DSBs) of genotoxic or physiologic origin in G1-phase cells. Each protein respectively is known to have unique functions during the repair of coding ends. I demonstrate here, however, that the kinase activities of Atm and DNA-PKcs redundantly drive normal and efficient coding joint formation. Furthermore, I also show that Atm and DNA-PKcs redundantly promote efficient processing and repair of signal ends both within the chromosome and on extrachromosomal excision circles. The overlapping functions of these two proteins during signal end repair also depend on redundant kinase activities. I also investigate the end processing and joining activities of potential shared substrates of the Atm and DNA-PKcs kinases during V(D)J recombination in order to better understand how Atm and DNA-PKcs orchestrate normal repair of both coding and signal ends. These candidate substrates include RAG-1 and RAG-2, which together comprise the nuclease that initiates V(D)J recombination, the chromatin-associated DNA repair factor 53BP1, and the DNA-PKcs protein itself. My findings indicate that Atm and DNA-PKcs have significantly broader roles in iii V(D)J recombination than previously appreciated. Moreover, these results have important implications for the general understanding of non-homologous end joining (NHEJ)-mediated DNA repair.

Language

English (en)

Chair and Committee

Barry P. Sleckman

Committee Members

Paul Allen, Susana Gonzalo, Eugene Oltz, Robder D. Schreiber, Sheila Stewart, Wojciech Swat

Comments

Permanent URL: https://doi.org/10.7936/K72F7KCZ

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