The Nonhomologous End joining (NHEJ) pathway repairs chromosome breaks. This pathway is thus critical in determining the effectiveness of front line cancer therapies, including ionizing radiation and certain chemotherapeutic drugs. NHEJ additionally has important roles in development of the adaptive immune response and the central nervous system, and mitigates accelerating aging phenotypes associated with the accumulation of unresolved damage. It is generally considered error prone, thus is expected to be a major contributor to radiation-induced mutation. Such mutations can in turn confer resistance to subsequent therapy in the primary cancer, and additionally cause secondary cancers. However, the extent to which mammalian NHEJ, and especially NHEJ-specific polymerases, contributes to mutation is not well understood. We will investigate here how two DNA polymerases specifically associated with NHEJ act to help mitigate NHEJ associated error. We will determine how each polymerase helps NHEJ balance flexibility and error, and how this balance is altered if one, the other, or both are defective or expression aberrantly regulated. Our results will provide a better framework for predicting the mutagenic side effects of cancer therapy, and help inform the appropriate application of therapy adjuncts that target specific repair pathways.
Cancer therapies like ionizing radiation kill tumors primarily through accumulation of lethal amounts of DNA damage, but damage is not always lethal (especially at tumor margins). An unavoidable consequence of therapy is thus DNA mutation;this proposal will describe how cells, both tumor and normal, protect DNA from radiation induced mutation. Our results will provide a better framework for predicting the mutagenic side effects of cancer therapy, and help inform the appropriate application of therapy adjuncts that target specific repair pathways.
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| Sastre-Moreno, Guillermo; Pryor, John M; Moreno-Oñate, Marta et al. (2017) Regulation of human pol? by ATM-mediated phosphorylation during non-homologous end joining. DNA Repair (Amst) 51:31-45 |
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| Ramsden, Dale A; Weed, Brett D; Reddy, Yeturu V R (2010) V(D)J recombination: Born to be wild. Semin Cancer Biol 20:254-60 |
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