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

Overview

MeSH Major

  • Aging
  • BRCA1 Protein
  • Cell Aging
  • DNA Breaks, Double-Stranded
  • DNA Repair
  • Oocytes
  • Ovary

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.

publication date

  • February 13, 2013

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC5130338

Digital Object Identifier (DOI)

  • 10.1126/scitranslmed.3004925

PubMed ID

  • 23408054

Additional Document Info

start page

  • 172ra21

volume

  • 5

number

  • 172