DNA repair execution is among the most important determinants of cancer etiology and response to therapy; mandating intimate knowledge of its molecular mechanisms and the vulnerabilities that present when it is altered. Cancer cells frequently harbor changes in their relative utilization (rewiring) of competing DNA repair mechanisms, and this has a profound influence on cancer genome evolution and clinical response to targeted agents. Prominent examples reside in hereditary breast and ovarian cancer syndrome and in a different spectrum of cancers that maintain telomere length through homologous recombination. Germline BRCA1 and BRCA2 gene mutations confer high penetrance breast and ovarian cancer. Both proteins are required for canonical, Rad51 dependent homologous recombination, thus accounting for the increased sensitivity to poly(ADP)ribose polymerase inhibitors (PARPi) exhibited by BRCA null tumors. Unfortunately, less than half of BRCA mutant cancers initially respond to PARPi and resistance invariably emerges in those that do. How DNA repair occurs in the context of BRCA dysfunction is therefore a question of central importance. Some clues exist as to the factors that influence this process. Namely, compelling genetic evidence indicates that hyperactivation of specific chromatin directed DNA repair mechanisms strongly influences genome integrity, cancer etiology, and response to therapy in BRCA mutant cells. To understand the biochemical basis for this phenomenon, my laboratory has developed approaches to identify the full spectrum of combinatorial nucleosome modifications that mediate recognition of damaged chromatin and directs utilization of specific DNA repair mechanisms. Notably, chromatin alterations also underlie the poorly understood phenomenon of alternative telomere lengthening (ALT), an evolutionarily conserved form of telomere maintenance that occurs in nearly 15% of human cancers. We have recently shown that ALT relies on BRCA-Rad51 independent homologous recombination and enacts dramatic changes in higher order chromatin structure to synthesize long telomere tracts in response to double-stranded DNA breaks. This was made possible by our development of methodologies to synchronously activate ALT and visualize every major step encompassing homologous recombination in real time at ALT telomeres. Interestingly, we observe overlapping genetic vulnerabilities in ALT and BRCA mutant cells, suggesting commonality in the repair processes that ensue in each scenario. Our overarching goals are to delineate molecular events necessary for canonical and alternative mechanisms of homologous recombination that arises in the setting of (1) therapeutic resistance in BRCA mutant cells, and (2) during ALT. These objectives will be performed in parallel and with equal emphasis. Our studies will yield fundamental advances to the understanding cancer genome integrity control and clarify new strategies to target underlying vulnerabilities in a broad range of malignancies. !
My research program is devoted to understanding fundamental mechanisms of genome integrity control and how they impact cancer etiology and response to therapy. We will continue to approach these central questions in cancer biology by utilizing unique systems that we have developed to investigate the molecular basis underlying (1) DNA damage recognition, (2) competition between canonical and alternative forms of DNA repair, and (3) response to targeted agents. These pursuits will provide invaluable insights into cancers that arise as a consequence of altered usage of DNA repair pathways, and their adaptive responses to DNA damaging therapies. !
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|Harding, Shane M; Greenberg, Roger A (2016) Choreographing the Double Strand Break Response: Ubiquitin and SUMO Control of Nuclear Architecture. Front Genet 7:103|
|Makvandi, Mehran; Xu, Kuiying; Lieberman, Brian P et al. (2016) A Radiotracer Strategy to Quantify PARP-1 Expression In Vivo Provides a Biomarker That Can Enable Patient Selection for PARP Inhibitor Therapy. Cancer Res 76:4516-24|
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