KAT2-mediated acetylation switches the mode of PALB2 chromatin association to safeguard genome integrity
- University of Oxford, United Kingdom
- Laval University, Canada
- University of Birmingham, United Kingdom
- 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
Jean-Yves Bleuyard
Anthony M Couturier
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
- Wolf-Dietrich Heyer, University of California, Davis, United States
Version history
- Preprint posted: August 15, 2019 (view preprint)
- Received: April 10, 2020
- Accepted: October 20, 2022
- Accepted Manuscript published: October 21, 2022 (version 1)
- 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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KAT2-mediated acetylation switches the mode of PALB2 chromatin association to safeguard genome integrity
eLife 11:e57736.
https://doi.org/10.7554/eLife.57736
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