The DNA Damage Checkpoint Eliminates Mouse Oocytes with Chromosome Synapsis Failure

Vera D. Rinaldi, Ewelina Bolcun-Filas, Hiroshi Kogo, Hiroki Kurahashi, John C. Schimenti

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Pairing and synapsis of homologous chromosomes during meiosis is crucial for producing genetically normal gametes and is dependent upon repair of SPO11-induced double-strand breaks (DSBs) by homologous recombination. To prevent transmission of genetic defects, diverse organisms have evolved mechanisms to eliminate meiocytes containing unrepaired DSBs or unsynapsed chromosomes. Here we show that the CHK2 (CHEK2)-dependent DNA damage checkpoint culls not only recombination-defective mouse oocytes but also SPO11-deficient oocytes that are severely defective in homolog synapsis. The checkpoint is triggered in oocytes that accumulate a threshold level of spontaneous DSBs (∼10) in late prophase I, the repair of which is inhibited by the presence of HORMAD1/2 on unsynapsed chromosome axes. Furthermore, Hormad2 deletion rescued the fertility of oocytes containing a synapsis-proficient, DSB repair-defective mutation in a gene (Trip13) required for removal of HORMADs from synapsed chromosomes, suggesting that many meiotic DSBs are normally repaired by intersister recombination in mice. Proper chromosome segregation during meiosis requires recombination repair of programmed DNA breaks to drive homolog pairing. Gametes with potentially devastating unsynapsed chromosomes or unrepaired breaks are killed. Surprisingly, Rinaldi et al. find that the CHK2 DNA damage checkpoint is important for eliminating mutant oocytes with either type of defect.

Original languageEnglish
Pages (from-to)1026-1036.e2
JournalMolecular Cell
Volume67
Issue number6
DOIs
Publication statusPublished - 21-09-2017

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Chromosome Pairing
DNA Damage
Oocytes
Chromosomes
Meiosis
Germ Cells
Genetic Recombination
Meiotic Prophase I
Recombinational DNA Repair
Chromosome Segregation
DNA Breaks
Homologous Recombination
Fertility
Mutation
Genes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Rinaldi, Vera D. ; Bolcun-Filas, Ewelina ; Kogo, Hiroshi ; Kurahashi, Hiroki ; Schimenti, John C. / The DNA Damage Checkpoint Eliminates Mouse Oocytes with Chromosome Synapsis Failure. In: Molecular Cell. 2017 ; Vol. 67, No. 6. pp. 1026-1036.e2.
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The DNA Damage Checkpoint Eliminates Mouse Oocytes with Chromosome Synapsis Failure. / Rinaldi, Vera D.; Bolcun-Filas, Ewelina; Kogo, Hiroshi; Kurahashi, Hiroki; Schimenti, John C.

In: Molecular Cell, Vol. 67, No. 6, 21.09.2017, p. 1026-1036.e2.

Research output: Contribution to journalArticle

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