NYMC Faculty Publications

Impairment of BRCA1-Related DNA Double-Strand Break Repair Leads to Ovarian Aging in Mice and Humans

Author Type(s)

Faculty

DOI

10.1126/scitranslmed.3004925

Journal Title

Science Translational Medicine

First Page

172

Last Page

172

Document Type

Article

Publication Date

2-13-2013

Department

Medicine

Keywords

Adolescent, Adult, Age Factors, Aging, Animals, Anti-Mullerian Hormone, BRCA1 Protein, BRCA2 Protein, Cellular Senescence, Child, Child, Preschool, DNA Breaks, Double-Stranded, DNA Repair, Female, Fertility, Gene Expression Regulation, Humans, Mice, Mice, Transgenic, Mutation, Oocytes, Ovary, RNA Interference, Young Adult

Disciplines

Medicine and Health Sciences

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.

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