3 years ago

The DNA Damage Checkpoint Eliminates Mouse Oocytes with Chromosome Synapsis Failure

The DNA Damage Checkpoint Eliminates Mouse Oocytes with Chromosome Synapsis Failure
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.

Graphical abstract

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Teaser

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.

Publisher URL: www.sciencedirect.com/science

DOI: S1097276517305737

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