Recent studies have shown a rising incidence and mortality for some cancers. These cancers are most commonly treated with clastogenic agents, such as ionizing radiation, leading to persistent double strand breaks (DSB) and mitotic catastrophe. One way to further sensitize tumor cells to these treatments is to capitalize on existing deficiencies in DSB repair. In order to do this, however, it is important to research how biological context influences DSB repair processes. Here, I have described DSB repair and the reporters developed, characterized, and utilized to understand such pathways (Chapters 1,2,3,5). Included throughout is a description of the novel use of these reporters to further understand DSB repair in three different contexts. First, I have shown that the 3'excision nuclease, ERCC1, is required for removal of a non-homologous segment during homology directed repair (HDR) (Chapter 3). Second, I have used the distinct resection requirements for HDR, single strand annealing (SSA), and alternative end joining (Alt-EJ) reporters to demonstrate the role of 53BP1 in limiting resection of a DSB. In addition, this data provides a mechanism by which loss of 53BP1 complements BRCA1-/- mediated deficiency in HDR (Chapter 4). Finally, I have determined that RAD50, DNA-PKcs and transcription state affect the mutagenic consequences during end joining repair, and that ATM limits incorrect end use in a transcription dependent manner (Chapter5). Each of these findings has an impact on current understanding of cancer etiology and treatment, and each demonstrates the importance of understanding the affects of biological context on DSB repair.
|Advisor:||Stark, Jeremy M.|
|Commitee:||Fischhaber, Paula, O'Connor, Timothy, Sam, Judy, Szabo, Piroska|
|School:||City of Hope's Irell & Manella Graduate School of Biomedical Sciences|
|Department:||Graduate School of Biological Sciences|
|School Location:||United States -- California|
|Source:||DAI-B 74/05(E), Dissertation Abstracts International|
|Subjects:||Biology, Molecular biology|
|Keywords:||DNA double strand break, Dna repair, Hdr, Nhej, Ssa, Transcription|
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