Novel mechanistic insights into the role of Mer2 as the keystone of meiotic DNA break formation

  1. Dorota Rousova
  2. Vaishnavi Nivsarkar
  3. Veronika Altmannova
  4. Vivek B Raina
  5. Saskia K Funk
  6. David Liedtke
  7. Petra Janning
  8. Franziska Müller
  9. Heidi Reichle
  10. Gerben Vader
  11. John Russell Weir  Is a corresponding author
  1. Friedrich Miescher Laboratory, Germany
  2. Max Planck Institute for Molecular Physiology, Germany
  3. Cancer Centre Amsterdam, Netherlands

Abstract

In meiosis, DNA double strand break (DSB) formation by Spo11 initiates recombination and enables chromosome segregation. Numerous factors are required for Spo11 activity, and couple the DSB machinery to the development of a meiosis-specific “axis-tethered loop” chromosome organization. Through in vitro reconstitution and budding yeast genetics we here provide architectural insight into the DSB machinery by focussing on a foundational DSB factor, Mer2. We characterise the interaction of Mer2 with the histone reader Spp1, and show that Mer2 directly associates to nucleosomes, likely highlighting a contribution of Mer2 to tethering DSB factors to chromatin. We reveal the biochemical basis of Mer2 association with Hop1, a HORMA domain-containing chromosomal axis factor. Finally, we identify a conserved region within Mer2 crucial for DSB activity, and show that this region of Mer2 interacts with the DSB factor Mre11. In combination with previous work, we establish Mer2 as a keystone of the DSB machinery by bridging key protein complexes involved in the initiation of meiotic recombination.

Data availability

Source data has been provided for the XL-MS experiments and for the IP-mass spec data

Article and author information

Author details

  1. Dorota Rousova

    Friedrich Miescher Laboratory, Tübingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7395-2596
  2. Vaishnavi Nivsarkar

    Department of Mechanistic Cell Biology, Max Planck Institute for Molecular Physiology, Dortmund, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Veronika Altmannova

    Friedrich Miescher Laboratory, Tübingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Vivek B Raina

    Department of Mechanistic Cell Biology, Max Planck Institute for Molecular Physiology, Dortmund, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Saskia K Funk

    Friedrich Miescher Laboratory, Tübingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. David Liedtke

    Friedrich Miescher Laboratory, Tübingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Petra Janning

    Department of Mechanistic Cell Biology, Max Planck Institute for Molecular Physiology, Dortmund, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Franziska Müller

    Department of Mechanistic Cell Biology, Max Planck Institute for Molecular Physiology, Dortmund, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Heidi Reichle

    Friedrich Miescher Laboratory, Tübingen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Gerben Vader

    Department of Human Genetics, Cancer Centre Amsterdam, Amsterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  11. John Russell Weir

    Friedrich Miescher Laboratory, Tübingen, Germany
    For correspondence
    john.weir@tuebingen.mpg.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6904-0284

Funding

Max-Planck-Gesellschaft

  • Dorota Rousova
  • Vaishnavi Nivsarkar
  • Veronika Altmannova
  • Vivek B Raina
  • Saskia K Funk
  • David Liedtke
  • Petra Janning
  • Franziska Müller
  • Heidi Reichle
  • Gerben Vader
  • John Russell Weir

Deutsche Forschungsgemeinschaft (WE 6513/2-1)

  • Saskia K Funk
  • John Russell Weir

H2020 European Research Council (638197)

  • Vaishnavi Nivsarkar
  • Vivek B Raina
  • Gerben Vader

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: July 30, 2020 (view preprint)
  2. Received: July 20, 2021
  3. Accepted: December 23, 2021
  4. Accepted Manuscript published: December 24, 2021 (version 1)
  5. Version of Record published: February 14, 2022 (version 2)

Copyright

© 2021, Rousova 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. Dorota Rousova
  2. Vaishnavi Nivsarkar
  3. Veronika Altmannova
  4. Vivek B Raina
  5. Saskia K Funk
  6. David Liedtke
  7. Petra Janning
  8. Franziska Müller
  9. Heidi Reichle
  10. Gerben Vader
  11. John Russell Weir
(2021)
Novel mechanistic insights into the role of Mer2 as the keystone of meiotic DNA break formation
eLife 10:e72330.
https://doi.org/10.7554/eLife.72330

Share this article

https://doi.org/10.7554/eLife.72330

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