The goal is to understand how cells repair double-strand DNA breaks with special emphasis on how this repair process is related to aging. Recent work has revealed that aging in Drosophila is correlated with pronounced changes in how double-strand breaks (DSBs) are repaired in the germ cells. Older males used a homologous repair pathway for more than 60% of their DSBs compared to less than 14% for young males where faster, more error-prone, pathways predominate. This project will determine whether these changes are part of a more general phenomenon linking aging with the cell's """"""""choice"""""""" of which DSB repair mechanism to use. The experiments make use of a well-tested system called """"""""Repair reporter 3"""""""" (Rr3) to measure the relative usage of individual DSB repair pathways in Drosophila. Specific questions to be answered are: 1. Do the age-related changes extend to the somatic cells? 2. Do they occur in both sexes? 3. Is the same age-specific pattern seen for DSBs formed anywhere in the genome? 4. Can these changes be explained by specific models, including stem cell regeneration or histone acetylation? 5. Do mutations and dietary supplements (resveratrol) which extend lifespan also modify age-related DSB repair? 6. How do certain DSB repair mutations affect the choice of repair pathway? Relevance: Repair of DNA damage, especially DSBs, is recognized as crucial to maintaining the stability of the genome. Human mutations in DSB repair genes have phenotypes including premature aging, radiosensitivity, immunodeficiency and cancer predisposition. These experiments will contribute to the understanding of DSB repair, especially its relationship to the aging process. ? ? ?
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