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

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.

Data availability

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.

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.

Metrics

  • 1,489
    views
  • 349
    downloads
  • 24
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Further reading

    1. Cell Biology
    2. Genetics and Genomics
    Keva Li, Nicholas Tolman ... UK Biobank Eye and Vision Consortium
    Research Article

    A glaucoma polygenic risk score (PRS) can effectively identify disease risk, but some individuals with high PRS do not develop glaucoma. Factors contributing to this resilience remain unclear. Using 4,658 glaucoma cases and 113,040 controls in a cross-sectional study of the UK Biobank, we investigated whether plasma metabolites enhanced glaucoma prediction and if a metabolomic signature of resilience in high-genetic-risk individuals existed. Logistic regression models incorporating 168 NMR-based metabolites into PRS-based glaucoma assessments were developed, with multiple comparison corrections applied. While metabolites weakly predicted glaucoma (Area Under the Curve = 0.579), they offered marginal prediction improvement in PRS-only-based models (p=0.004). We identified a metabolomic signature associated with resilience in the top glaucoma PRS decile, with elevated glycolysis-related metabolites—lactate (p=8.8E-12), pyruvate (p=1.9E-10), and citrate (p=0.02)—linked to reduced glaucoma prevalence. These metabolites combined significantly modified the PRS-glaucoma relationship (Pinteraction = 0.011). Higher total resilience metabolite levels within the highest PRS quartile corresponded to lower glaucoma prevalence (Odds Ratiohighest vs. lowest total resilience metabolite quartile=0.71, 95% Confidence Interval = 0.64–0.80). As pyruvate is a foundational metabolite linking glycolysis to tricarboxylic acid cycle metabolism and ATP generation, we pursued experimental validation for this putative resilience biomarker in a human-relevant Mus musculus glaucoma model. Dietary pyruvate mitigated elevated intraocular pressure (p=0.002) and optic nerve damage (p<0.0003) in Lmx1bV265D mice. These findings highlight the protective role of pyruvate-related metabolism against glaucoma and suggest potential avenues for therapeutic intervention.

    1. Cell Biology
    2. Immunology and Inflammation
    Alejandro Rosell, Agata Adelajda Krygowska ... Esther Castellano Sanchez
    Research Article

    Macrophages are crucial in the body’s inflammatory response, with tightly regulated functions for optimal immune system performance. Our study reveals that the RAS–p110α signalling pathway, known for its involvement in various biological processes and tumourigenesis, regulates two vital aspects of the inflammatory response in macrophages: the initial monocyte movement and later-stage lysosomal function. Disrupting this pathway, either in a mouse model or through drug intervention, hampers the inflammatory response, leading to delayed resolution and the development of more severe acute inflammatory reactions in live models. This discovery uncovers a previously unknown role of the p110α isoform in immune regulation within macrophages, offering insight into the complex mechanisms governing their function during inflammation and opening new avenues for modulating inflammatory responses.