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KAT5 tyrosine phosphorylation couples chromatin sensing to ATM signalling

Nature volume 498, pages 70–74 (2013)Cite this article

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A Retraction to this article was published on 11 April 2019

Abstract

The detection of DNA lesions within chromatin represents a critical step in cellular responses to DNA damage. However, the regulatory mechanisms that couple chromatin sensing to DNA-damage signalling in mammalian cells are not well understood. Here we show that tyrosine phosphorylation of the protein acetyltransferase KAT5 (also known as TIP60) increases after DNA damage in a manner that promotes KAT5 binding to the histone mark H3K9me3. This triggers KAT5-mediated acetylation of the ATM kinase, promoting DNA-damage-checkpoint activation and cell survival. We also establish that chromatin alterations can themselves enhance KAT5 tyrosine phosphorylation and ATM-dependent signalling, and identify the proto-oncogene c-Abl as a mediator of this modification. These findings define KAT5 tyrosine phosphorylation as a key event in the sensing of genomic and chromatin perturbations, and highlight a key role for c-Abl in such processes.

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Figure 1: KAT5 phosphorylation enhances its binding to H3K9me3.
Figure 2: KAT5 Tyr phosphorylation promotes ATM activation, checkpoint signalling and cell survival after ionizing radiation.
Figure 3: Chromatin alterations activate KAT5 phosphorylation and checkpoint signalling.
Figure 4: Chromatin binding promotes KAT5 phosphorylation.
Figure 5: c-Abl-dependent KAT5 tyrosine phosphorylation.

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Acknowledgements

We thank all members of the Jackson laboratory for help and support, and A. Blackford, S. Britton, K. Dry, J. Forment and J. Travers for critical reading of the manuscript. Research in the Jackson laboratory is funded by Cancer Research UK program grant C6/A11224, the European Research Council and the European Community Seventh Framework Programme grant agreement no. HEALTH-F2-2010-259893 (DDR). Core funding is provided by CRUK (C6946/A14492) and the Wellcome Trust (WT092096). S.P.J. receives his salary from the University of Cambridge, UK, supplemented by CRUK. A.K. is funded by a Herchel Smith Fellowship from the University of Cambridge.

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Authors and Affiliations

  1. The Gurdon Institute and Department of Biochemistry, University of Cambridge, Tennis Court Road, CB2 1QN, Cambridge, UK

    Abderrahmane Kaidi & Stephen P. Jackson

  2. The Wellcome Trust Sanger Institute, CB10 1SA, Hinxton, Cambridge, UK

    Stephen P. Jackson

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  1. Abderrahmane Kaidi
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Contributions

All experiments were conceived by A.K. and S.P.J. and were carried out by A.K. S.P.J. and A.K. wrote the paper.

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Correspondence to Stephen P. Jackson.

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The authors declare no competing financial interests.

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Kaidi, A., Jackson, S. KAT5 tyrosine phosphorylation couples chromatin sensing to ATM signalling. Nature 498, 70–74 (2013). https://doi.org/10.1038/nature12201

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