1. Cell Biology
  2. Genetics and Genomics

Phosphoregulation of DSB-1 mediates control of meiotic double-strand break activity

  1. Heyun Guo
  2. Ericca L Stamper
  3. Aya Sato-Carlton
  4. Masa A Shimazoe
  5. Xuan Li
  6. Liangyu Zhang
  7. Lewis Stevens
  8. KC Jacky Tam
  9. Abby F Dernburg
  10. Peter M Carlton  Is a corresponding author
  1. Kyoto University, Japan
  2. University of California, Berkeley, United States
  3. University of Edinburgh, United Kingdom
https://doi.org/10.7554/eLife.77956
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Cite this article
  1. Heyun Guo
  2. Ericca L Stamper
  3. Aya Sato-Carlton
  4. Masa A Shimazoe
  5. Xuan Li
  6. Liangyu Zhang
  7. Lewis Stevens
  8. KC Jacky Tam
  9. Abby F Dernburg
  10. Peter M Carlton
(2022)
Phosphoregulation of DSB-1 mediates control of meiotic double-strand break activity
eLife 11:e77956.
https://doi.org/10.7554/eLife.77956
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Abstract

In the first meiotic cell division, proper segregation of chromosomes in most organisms depends on chiasmata, exchanges of continuity between homologous chromosomes that originate from the repair of programmed double-strand breaks (DSBs) catalyzed by the Spo11 endonuclease. Since DSBs can lead to irreparable damage in germ cells, while chromosomes lacking DSBs also lack chiasmata, the number of DSBs must be carefully regulated to be neither too high nor too low. Here, we show that in Caenorhabditis elegans, meiotic DSB levels are controlled by the phosphoregulation of DSB-1, a homolog of the yeast Spo11 cofactor Rec114, by the opposing activities of PP4PPH-4.1 phosphatase and ATRATL-1 kinase. Increased DSB-1 phosphorylation in pph-4.1 mutants correlates with reduction in DSB formation, while prevention of DSB-1 phosphorylation drastically increases the number of meiotic DSBs both in pph-4.1 mutants as well as in the wild type background. C. elegans and its close relatives also possess a diverged paralog of DSB-1, called DSB-2, and loss of dsb-2 is known to reduce DSB formation in oocytes with increasing age. We show that the proportion of the phosphorylated, and thus inactivated, form of DSB-1 increases with age and upon loss of DSB-2, while non-phosphorylatable DSB-1 rescues the age-dependent decrease in DSBs in dsb-2 mutants. These results suggest that DSB-2 evolved in part to compensate for the inactivation of DSB-1 through phosphorylation, to maintain levels of DSBs in older animals. Our work shows that PP4PPH-4.1, ATRATL-1, and DSB-2 act in concert with DSB-1 to promote optimal DSB levels throughout the reproductive lifespan.

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All data generated or analysed during this study are included in the manuscript and supporting files; numerical Source Data files have been provided for all plots and graphs

Article and author information

Author details

  1. Heyun Guo

    Graduate School of Biostudies, Kyoto University, Kyoto, Japan
    Competing interests
    The authors declare that no competing interests exist.

  2. Ericca L Stamper

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Aya Sato-Carlton

    Graduate School of Biostudies, Kyoto University, Kyoto, Japan
    Competing interests
    The authors declare that no competing interests exist.

  4. Masa A Shimazoe

    Graduate School of Biostudies, Kyoto University, Kyoto, Japan
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2018-0497

  5. Xuan Li

    Graduate School of Biostudies, Kyoto University, Kyoto, Japan
    Competing interests
    The authors declare that no competing interests exist.

  6. Liangyu Zhang

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2701-0773

  7. Lewis Stevens

    Institute of Evolutionary Biology, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6075-8273

  8. KC Jacky Tam

    Graduate School of Biostudies, Kyoto University, Kyoto, Japan
    Competing interests
    The authors declare that no competing interests exist.

  9. Abby F Dernburg

    Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8037-1079

  10. Peter M Carlton

    Graduate School of Biostudies, Kyoto University, Kyoto, Japan
    For correspondence
    carlton.petermark.3v@kyoto-u.ac.jp
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5320-6024

Funding

Japan Society for the Promotion of Science (5H04328)

  • Peter M Carlton

Japan Society for the Promotion of Science (17K15064)

  • Aya Sato-Carlton

Howard Hughes Medical Institute

  • Abby F Dernburg

Naito Foundation

  • Aya Sato-Carlton

Ministry of Education, Culture, Sports, Science and Technology

  • Heyun Guo

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Federico Pelisch, University of Dundee, United Kingdom

Version history

  1. Preprint posted: February 17, 2022 (view preprint)
  2. Received: February 17, 2022
  3. Accepted: June 23, 2022
  4. Accepted Manuscript published: June 27, 2022 (version 1)
  5. Version of Record published: July 13, 2022 (version 2)

Copyright

© 2022, Guo et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Heyun Guo
  2. Ericca L Stamper
  3. Aya Sato-Carlton
  4. Masa A Shimazoe
  5. Xuan Li
  6. Liangyu Zhang
  7. Lewis Stevens
  8. KC Jacky Tam
  9. Abby F Dernburg
  10. Peter M Carlton
(2022)
Phosphoregulation of DSB-1 mediates control of meiotic double-strand break activity
eLife 11:e77956.
https://doi.org/10.7554/eLife.77956

Share this article

https://doi.org/10.7554/eLife.77956

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