Distinct DNA-damage-dependent and -independent responses drive the loss of oocytes in recombination-defective mouse mutants

Monica Di Giacomo, Marco Barchi, Frédéric Baudat, Winfried Edelmann, Scott Keeney, Maria Jasin

Research output: Contribution to journalArticlepeer-review

163 Scopus citations

Abstract

Defects in meiotic recombination in many organisms result in arrest because of activation of a meiotic checkpoint(s). The proximal defect that triggers this checkpoint in mammalian germ cells is not understood, but it has been suggested to involve either the presence of DNA damage in the form of unrepaired recombination intermediates or defects in homologous chromosome pairing and synapsis independent of DNA damage per se. To distinguish between these possibilities in the female germ line, we compared mouse oocyte development in a mutant that fails to form the double-strand breaks (DSBs) that initiate meiotic recombination (Spo11-/-) to mutants with defects in processing DSBs when they are formed (Dmc1-/- and Msh5-/-), and we examined the epistasis relationships between these mutations. Absence of DSB formation caused a partial defect in follicle formation, whereas defects in DSB repair caused earlier and more severe meiotic arrest, which could be suppressed by eliminating DSB formation. Therefore, our analysis reveals that there are both DNA-damage-dependent and -independent responses to recombination errors in mammalian oocytes. By using these findings as a paradigm, we also examined oocyte loss in mutants lacking the DNA-damage checkpoint kinase ATM. The absence of ATM caused defects in folliculogenesis that were similar to those in Dmc1 mutants and that could be suppressed by Spo11 mutation, implying that oocyte death in Atm-deficient animals is a response to defective DSB repair.

Original languageEnglish (US)
Pages (from-to)737-742
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number3
DOIs
StatePublished - Jan 18 2005

Keywords

  • Dmc1
  • Msh5
  • Spo11

ASJC Scopus subject areas

  • General

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