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

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...

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Autores principales: ElInati, Elias, Zielinska, Agata P., McCarthy, Afshan, Kubikova, Nada, Maciulyte, Valdone, Mahadevaiah, Shantha, Sangrithi, Mahesh N., Ojarikre, Obah, Wells, Dagan, Niakan, Kathy K., Schuh, Melina, Turner, James M. A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248069/
https://www.ncbi.nlm.nih.gov/pubmed/32451402
http://dx.doi.org/10.1038/s41467-020-16441-z
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author ElInati, Elias
Zielinska, Agata P.
McCarthy, Afshan
Kubikova, Nada
Maciulyte, Valdone
Mahadevaiah, Shantha
Sangrithi, Mahesh N.
Ojarikre, Obah
Wells, Dagan
Niakan, Kathy K.
Schuh, Melina
Turner, James M. A.
author_facet ElInati, Elias
Zielinska, Agata P.
McCarthy, Afshan
Kubikova, Nada
Maciulyte, Valdone
Mahadevaiah, Shantha
Sangrithi, Mahesh N.
Ojarikre, Obah
Wells, Dagan
Niakan, Kathy K.
Schuh, Melina
Turner, James M. A.
author_sort ElInati, Elias
collection PubMed
description 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.
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spelling pubmed-72480692020-06-03 The BCL-2 pathway preserves mammalian genome integrity by eliminating recombination-defective oocytes ElInati, Elias Zielinska, Agata P. McCarthy, Afshan Kubikova, Nada Maciulyte, Valdone Mahadevaiah, Shantha Sangrithi, Mahesh N. Ojarikre, Obah Wells, Dagan Niakan, Kathy K. Schuh, Melina Turner, James M. A. Nat Commun Article 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. Nature Publishing Group UK 2020-05-25 /pmc/articles/PMC7248069/ /pubmed/32451402 http://dx.doi.org/10.1038/s41467-020-16441-z Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
ElInati, Elias
Zielinska, Agata P.
McCarthy, Afshan
Kubikova, Nada
Maciulyte, Valdone
Mahadevaiah, Shantha
Sangrithi, Mahesh N.
Ojarikre, Obah
Wells, Dagan
Niakan, Kathy K.
Schuh, Melina
Turner, James M. A.
The BCL-2 pathway preserves mammalian genome integrity by eliminating recombination-defective oocytes
title The BCL-2 pathway preserves mammalian genome integrity by eliminating recombination-defective oocytes
title_full The BCL-2 pathway preserves mammalian genome integrity by eliminating recombination-defective oocytes
title_fullStr The BCL-2 pathway preserves mammalian genome integrity by eliminating recombination-defective oocytes
title_full_unstemmed The BCL-2 pathway preserves mammalian genome integrity by eliminating recombination-defective oocytes
title_short The BCL-2 pathway preserves mammalian genome integrity by eliminating recombination-defective oocytes
title_sort bcl-2 pathway preserves mammalian genome integrity by eliminating recombination-defective oocytes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248069/
https://www.ncbi.nlm.nih.gov/pubmed/32451402
http://dx.doi.org/10.1038/s41467-020-16441-z
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