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.
| Pryor, John M; Conlin, Michael P; Carvajal-Garcia, Juan et al. (2018) Ribonucleotide incorporation enables repair of chromosome breaks by nonhomologous end joining. Science 361:1126-1129 |
| 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 |
| Conlin, Michael P; Reid, Dylan A; Small, George W et al. (2017) DNA Ligase IV Guides End-Processing Choice during Nonhomologous End Joining. Cell Rep 20:2810-2819 |
| Wyatt, David W; Feng, Wanjuan; Conlin, Michael P et al. (2016) Essential Roles for Polymerase ?-Mediated End Joining in the Repair of Chromosome Breaks. Mol Cell 63:662-673 |
| Pryor, John M; Waters, Crystal A; Aza, Ana et al. (2015) Essential role for polymerase specialization in cellular nonhomologous end joining. Proc Natl Acad Sci U S A 112:E4537-45 |
| Moon, Andrea F; Pryor, John M; Ramsden, Dale A et al. (2014) Sustained active site rigidity during synthesis by human DNA polymerase ?. Nat Struct Mol Biol 21:253-60 |
| Yousefzadeh, Matthew J; Wyatt, David W; Takata, Kei-Ichi et al. (2014) Mechanism of suppression of chromosomal instability by DNA polymerase POLQ. PLoS Genet 10:e1004654 |
| Waters, Crystal A; Strande, Natasha T; Wyatt, David W et al. (2014) Nonhomologous end joining: a good solution for bad ends. DNA Repair (Amst) 17:39-51 |
| Ramsden, Dale A (2011) Polymerases in nonhomologous end joining: building a bridge over broken chromosomes. Antioxid Redox Signal 14:2509-19 |
| 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 |
Showing the most recent 10 out of 19 publications
