title: Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans.
abstract: The underlying mechanism behind age-induced wastage of the human ovarian follicle reserve is unknown. We identify impaired ATM (ataxia-telangiectasia 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, declines 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, whereas 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-Müllerian hormone. These data implicate DNA DSB repair efficiency as an important determinant of oocyte aging in women.
authors: Institute for Reproductive Medicine and Fertility Preservation, and Laboratory of Molecular Reproduction, Department of Obstetrics and Gynecology, New York Medical College, Rye, NY 10580, USA.
authors: Shiny
authors: S
authors: Titus
authors: Fang
authors: F
authors: Li
authors: Robert
authors: R
authors: Stobezki
authors: Komala
authors: K
authors: Akula
authors: Evrim
authors: E
authors: Unsal
authors: Kyungah
authors: K
authors: Jeong
authors: Maura
authors: M
authors: Dickler
authors: Mark
authors: M
authors: Robson
authors: Fred
authors: F
authors: Moy
authors: Sumanta
authors: S
authors: Goswami
authors: Kutluk
authors: K
authors: Oktay
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D054304:Anti-Mullerian Hormone / Q000097:blood; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D024682:BRCA2 Protein / Q000235:genetics / Q000378:metabolism; D016922:Cellular Senescence; D002648:Child; D002675:Child, Preschool; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D005260:Female; D005298:Fertility; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009865:Oocytes / Q000378:metabolism* / Q000473:pathology; D010053:Ovary / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D034622:RNA Interference; D055815:Young Adult
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D054304:Anti-Mullerian Hormone