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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM030948-28
Application #
8118971
Study Section
Development - 2 Study Section (DEV2)
Program Officer
Janes, Daniel E
Project Start
1982-07-01
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
28
Fiscal Year
2011
Total Cost
$538,386
Indirect Cost
Name
University of Wisconsin Madison
Department
Genetics
Type
Schools of Earth Sciences/Natur
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Engels, William R (2009) Exact tests for Hardy-Weinberg proportions. Genetics 183:1431-41
Johnson-Schlitz, Dena M; Flores, Carlos; Engels, William R (2007) Multiple-pathway analysis of double-strand break repair mutations in Drosophila. PLoS Genet 3:e50
Preston, Christine R; Flores, Carlos C; Engels, William R (2006) Differential usage of alternative pathways of double-strand break repair in Drosophila. Genetics 172:1055-68
Preston, Christine R; Flores, Carlos; Engels, William R (2006) Age-dependent usage of double-strand-break repair pathways. Curr Biol 16:2009-15
Johnson-Schlitz, Dena M; Engels, William R (2006) The effect of gap length on double-strand break repair in Drosophila. Genetics 173:2033-8
Johnson-Schlitz, Dena; Engels, William R (2006) Template disruptions and failure of double Holliday junction dissolution during double-strand break repair in Drosophila BLM mutants. Proc Natl Acad Sci U S A 103:16840-5
Ciapponi, Laura; Cenci, Giovanni; Ducau, Judith et al. (2004) The Drosophila Mre11/Rad50 complex is required to prevent both telomeric fusion and chromosome breakage. Curr Biol 14:1360-6
Preston, Christine R; Engels, William; Flores, Carlos (2002) Efficient repair of DNA breaks in Drosophila: evidence for single-strand annealing and competition with other repair pathways. Genetics 161:711-20
Kusano, K; Johnson-Schlitz, D M; Engels, W R (2001) Sterility of Drosophila with mutations in the Bloom syndrome gene--complementation by Ku70. Science 291:2600-2
Flores, C; Engels, W (1999) Microsatellite instability in Drosophila spellchecker1 (MutS homolog) mutants. Proc Natl Acad Sci U S A 96:2964-9

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