Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans

Shiny Titus, Fang Li, Robert Stobezki, Komala Akula, Evrim Unsal, Kyungah Jeong, Maura Dickler, Mark Robson, Fred Moy, Sumanta Goswami, Kutluk Oktay

Research output: Contribution to journalArticlepeer-review

279 Scopus citations

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 wildtype 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.

Original languageEnglish
Article number172ra21
JournalScience Translational Medicine
Volume5
Issue number172
DOIs
StatePublished - 13 Feb 2013

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