KAT2-mediated acetylation switches the mode of PALB2 chromatin association to safeguard genome integrity

  1. Marjorie Fournier  Is a corresponding author
  2. Amélie Rodrigue
  3. Larissa Milano
  4. Jean-Yves Bleuyard
  5. Anthony M Couturier
  6. Jacob Wall
  7. Jessica Ellins
  8. Svenja Hester
  9. Stephen J Smerdon
  10. László Tora
  11. Jean-Yves Masson  Is a corresponding author
  12. Fumiko Esashi  Is a corresponding author
  1. University of Oxford, United Kingdom
  2. Laval University, Canada
  3. University of Birmingham, United Kingdom
  4. Institut de Génétique et de Biologie Moléculaire et Cellulaire, France

Abstract

The tumour suppressor PALB2 stimulates RAD51-mediated homologous recombination (HR) repair of DNA damage, whilst its steady-state association with active genes protects these loci from replication stress. Here, we report that the lysine acetyltransferases 2A and 2B (KAT2A/2B, also called GCN5/PCAF), two well-known transcriptional regulators, acetylate a cluster of seven lysine residues (7K-patch) within the PALB2 chromatin association motif (ChAM) and, in this way, regulate context-dependent PALB2 binding to chromatin. In unperturbed cells, the 7K-patch is targeted for KAT2A/2B-mediated acetylation, which in turn enhances the direct association of PALB2 with nucleosomes. Importantly, DNA damage triggers a rapid deacetylation of ChAM and increases the overall mobility of PALB2. Distinct missense mutations of the 7K-patch render the mode of PALB2 chromatin binding, making it either unstably chromatin-bound (7Q) or randomly bound with a reduced capacity for mobilisation (7R). Significantly, both of these mutations confer a deficiency in RAD51 foci formation and increase DNA damage in S phase, leading to the reduction of overall cell survival. Thus, our study reveals that acetylation of the ChAM 7K-patch acts as a molecular switch to enable dynamic PALB2 shuttling for HR repair while protecting active genes during DNA replication.

Data availability

The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE (Perez-Riverol et al, 2019) partner repository with the dataset identifier PXD014678 and PXD014681. All other data generated or analysed during this study are included in the manuscript and supporting file. Raw images of western blots and DNA/protein gels are avilable through the Open Science Framework, with the following link: https://osf.io/8e9ms/?view_only=3908731b938e4751af7518744f3ff584

Article and author information

Author details

  1. Marjorie Fournier

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    For correspondence
    marjorie.fournier@path.ox.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
  2. Amélie Rodrigue

    Department of Molecular Biology, Laval University, Québec, Canada
    Competing interests
    The authors declare that no competing interests exist.
  3. Larissa Milano

    Department of Molecular Biology, Laval University, Québec, Canada
    Competing interests
    The authors declare that no competing interests exist.
  4. Jean-Yves Bleuyard

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6727-5362
  5. Anthony M Couturier

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1512-9558
  6. Jacob Wall

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Jessica Ellins

    Department of Biochemistry, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Svenja Hester

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Stephen J Smerdon

    Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. László Tora

    Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7398-2250
  11. Jean-Yves Masson

    Department of Molecular Biology, Laval University, Québec, Canada
    For correspondence
    Jean-Yves.Masson@crchudequebec.ulaval.ca
    Competing interests
    The authors declare that no competing interests exist.
  12. Fumiko Esashi

    Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom
    For correspondence
    fumiko.esashi@path.ox.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0902-2364

Funding

Wellcome Trust ((101009/Z/13/Z)

  • Fumiko Esashi

Cancer Research UK (FC001156))

  • Stephen J Smerdon

Medical Research Council (FC001156))

  • Stephen J Smerdon

Wellcome Trust (FC001156)

  • Stephen J Smerdon

H2020 European Research Council (ERC-2013-340551)

  • László Tora

Edward P Abraham Research Fund (RF 260)

  • Fumiko Esashi

Canadian Institutes of Health Research (FDN-388879)

  • Jean-Yves Masson

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

Reviewing Editor

  1. Wolf-Dietrich Heyer, University of California, Davis, United States

Version history

  1. Preprint posted: August 15, 2019 (view preprint)
  2. Received: April 10, 2020
  3. Accepted: October 20, 2022
  4. Accepted Manuscript published: October 21, 2022 (version 1)
  5. Version of Record published: November 17, 2022 (version 2)

Copyright

© 2022, Fournier 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. Marjorie Fournier
  2. Amélie Rodrigue
  3. Larissa Milano
  4. Jean-Yves Bleuyard
  5. Anthony M Couturier
  6. Jacob Wall
  7. Jessica Ellins
  8. Svenja Hester
  9. Stephen J Smerdon
  10. László Tora
  11. Jean-Yves Masson
  12. Fumiko Esashi
(2022)
KAT2-mediated acetylation switches the mode of PALB2 chromatin association to safeguard genome integrity
eLife 11:e57736.
https://doi.org/10.7554/eLife.57736

Share this article

https://doi.org/10.7554/eLife.57736

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