151. Ovarian aging: breaking up is hard to fix
- Author
-
Joshua Johnson and David L. Keefe
- Subjects
Genetics ,Aging ,endocrine system diseases ,DNA Repair ,DNA repair ,BRCA1 Protein ,genetic processes ,Ovary ,Cellular senescence ,General Medicine ,Biology ,Article ,Cell biology ,enzymes and coenzymes (carbohydrates) ,Dna breaks ,Oocytes ,Animals ,Humans ,DNA Breaks, Double-Stranded ,Female ,biological phenomena, cell phenomena, and immunity ,Double stranded ,Cellular Senescence - Abstract
The underlying mechanism behind age-induced wastage of the human ovarian follicle reserve is unknown. In this study, we identify impaired ATM (ataxia-telengiectasia mutated)-mediated DNA double strand break (DSB) repair as a cause of aging in mouse and human oocytes. We show that DSBs accumulate in primordial follicles with age. In parallel, expression of key DNA DSB repair genes BRCA1, MRE11, Rad51, and ATM, but not BRCA2, decline in single mouse and human oocytes. In BRCA1-deficient mice, reproductive capacity was impaired, primordial follicle counts were lower, and DSBs were increased in remaining follicles with age relative to wild-type mice. Furthermore, oocyte-specific knockdown of BRCA1, MRE11, Rad51 and ATM expression increased DSBs and reduced survival while BRCA1 overexpression enhanced both parameters. Likewise, ovarian reserve was impaired in young women with germline BRCA1 mutations compared to controls as determined by serum concentrations of anti-mullerian hormone. These data implicate DNA DSB repair efficiency as an important determinant of oocyte aging in women.
- Published
- 2013