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

Author

Listed:
  • 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
    IVI-RMA)

  • Valdone Maciulyte

    (The Francis Crick Institute)

  • Shantha Mahadevaiah

    (The Francis Crick Institute)

  • Mahesh N. Sangrithi

    (Duke-NUS Graduate Medical School
    KK Women’s and Children’s Hospital)

  • Obah Ojarikre

    (The Francis Crick Institute)

  • Dagan Wells

    (University of Oxford
    IVI-RMA)

  • Kathy K. Niakan

    (The Francis Crick Institute)

  • Melina Schuh

    (Max Planck Institute for Biophysical Chemistry)

  • James M. A. Turner

    (The Francis Crick Institute)

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.

Suggested Citation

  • 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 & Ja, 2020. "The BCL-2 pathway preserves mammalian genome integrity by eliminating recombination-defective oocytes," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16441-z
    DOI: 10.1038/s41467-020-16441-z
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