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

Elias ElInati, Agata P. Zielinska, Afshan McCarthy, Nada Kubikova, Valdone Maciulyte, Shantha Mahadevaiah, Mahesh N. Sangrithi, Obah Ojarikre, Dagan Wells, Kathy K. Niakan, Melina Schuh and James M. A. Turner ()
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Elias ElInati: The Francis Crick Institute
Agata P. Zielinska: Max Planck Institute for Biophysical Chemistry
Afshan McCarthy: The Francis Crick Institute
Nada Kubikova: University of Oxford
Valdone Maciulyte: The Francis Crick Institute
Shantha Mahadevaiah: The Francis Crick Institute
Mahesh N. Sangrithi: Duke-NUS Graduate Medical School
Obah Ojarikre: The Francis Crick Institute
Dagan Wells: University of Oxford
Kathy K. Niakan: The Francis Crick Institute
Melina Schuh: Max Planck Institute for Biophysical Chemistry
James M. A. Turner: The Francis Crick Institute

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-16441-z

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