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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Pelroy, Richard
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
Zip Code
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
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
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
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
Burkhalter, Martin D; Roberts, Steven A; Havener, Jody M et al. (2009) Activity of ribonucleotide reductase helps determine how cells repair DNA double strand breaks. DNA Repair (Amst) 8:1258-63
Garcia-Diaz, Miguel; Bebenek, Katarzyna; Larrea, Andres A et al. (2009) Template strand scrunching during DNA gap repair synthesis by human polymerase lambda. Nat Struct Mol Biol 16:967-72
Mueller, Geoffrey A; Moon, Andrea F; Derose, Eugene F et al. (2008) A comparison of BRCT domains involved in nonhomologous end-joining: introducing the solution structure of the BRCT domain of polymerase lambda. DNA Repair (Amst) 7:1340-51
Davis, Bryan J; Havener, Jody M; Ramsden, Dale A (2008) End-bridging is required for pol mu to efficiently promote repair of noncomplementary ends by nonhomologous end joining. Nucleic Acids Res 36:3085-94
DeRose, Eugene F; Clarkson, Michael W; Gilmore, Steven A et al. (2007) Solution structure of polymerase mu's BRCT Domain reveals an element essential for its role in nonhomologous end joining. Biochemistry 46:12100-10

Showing the most recent 10 out of 14 publications