The BCL-2 pathway preserves mammalian genome integrity by eliminating recombination-defective oocytes

Abstract

DNA double-strand breaks (DSBs) are toxic to mammalian cells. However, during meiosis, more than 200 DSBs are generated deliberately, to ensure reciprocal recombination and orderly segregation of homologous chromosomes. If left unrepaired, meiotic DSBs can cause aneuploidy in gametes and compromise viability in offspring. Oocytes in which DSBs persist are therefore eliminated by the DNA-damage checkpoint. Here we show that the DNA-damage checkpoint eliminates oocytes via the pro-apoptotic BCL-2 pathway members Puma, Noxa and Bax. Deletion of these factors prevents oocyte elimination in recombination-repair mutants, even when the abundance of unresolved DSBs is high. Remarkably, surviving oocytes can extrude a polar body and be fertilised, despite chaotic chromosome segregation at the first meiotic division. Our findings raise the possibility that allelic variants of the BCL-2 pathway could influence the risk of embryonic aneuploidy.

If left unrepaired, meiotic DSBs are toxic to mammalian cells, thus oocytes in which DSBs persist are eliminated by the DNA-damage checkpoint. Here the authors provide insights into the roles of PUMA, NOXA and BAX during DNA damage checkpoint that eliminates Dmc1^−/− and Msh5^−/− oocytes.