NSF Award
0346354
Double-strand breaks (DSBs) are lesions that arise in DNA as a result of exogenous insults (e.g., radiation and drug therapies) and normal metabolic processes (e.g., DNA replication). Mammalian cells (e.g., mouse and human cells) can use homologous recombination (HR) as one method to repair DSBs. In HR, the damaged DNA molecule uses a very similar or identical, but undamaged DNA molecule to guide the repair process. This is considered to be a very precise method of repair. In addition to HR, there are other DSB repair pathways, including nonhomologous end-joining (NHEJ) in which ends are simply rejoined, often with the loss of sequence information. The research in this project is aimed at understanding mechanisms of DSB repair by HR in mammalian cells to provide insight into how it precisely repairs damaged DNA without creating genomic alterations. Another issue regards the influence of different DSB repair pathways on each other. Loss of NHEJ leads to elevated levels of HR. This project will address whether the DNA ends are processed differently when there is loss of NHEJ and how this affects HR. Deficiency of HR, by loss of HR proteins, will also be examined, to try to discern the exact step that is affected by loss of individual HR proteins. Understanding mechanisms of HR, its interrelationship with NHEJ, and the role of the protein components involved in these processes will provide insight into how genomic integrity is maintained. The project will also involve the training of graduate students and postdoctoral research associates.
