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Activation of ATM depends on chromatin interactions occurring before induction of DNA damage

Nature Cell Biology volume 11, pages 92–96 (2009)Cite this article

Abstract

Efficient and correct responses to double-stranded breaks (DSB) in chromosomal DNA are crucial for maintaining genomic stability and preventing chromosomal alterations that lead to cancer1,2. The generation of DSB is associated with structural changes in chromatin and the activation of the protein kinase ataxia-telangiectasia mutated (ATM), a key regulator of the signalling network of the cellular response to DSB3,4. The interrelationship between DSB-induced changes in chromatin architecture and the activation of ATM is unclear4. Here we show that the nucleosome-binding protein HMGN1 modulates the interaction of ATM with chromatin both before and after DSB formation, thereby optimizing its activation. Loss of HMGN1 or ablation of its ability to bind to chromatin reduces the levels of ionizing radiation (IR)-induced ATM autophosphorylation and the activation of several ATM targets. IR treatments lead to a global increase in the acetylation of Lys 14 of histone H3 (H3K14) in an HMGN1-dependent manner and treatment of cells with histone deacetylase inhibitors bypasses the HMGN1 requirement for efficient ATM activation. Thus, by regulating the levels of histone modifications, HMGN1 affects ATM activation. Our studies identify a new mediator of ATM activation and demonstrate a direct link between the steady-state intranuclear organization of ATM and the kinetics of its activation after DNA damage.

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Figure 1: Loss of HMGN1 impairs IR-induced ATM autophosphorylation and activation.
Figure 2: Enhanced ATM chromatin retention in Hmgn1−/− cells.
Figure 3: HMGN1 enhances ATM activation by binding to chromatin.
Figure 4: HMGN1 modulates the interaction of ATM with chromatin.

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Acknowledgements

We thank A. Celeste (NCI) for advice and help, and S. Garfield (Confocal Core Facility of the LEC, NCI), for help with imaging. The research was supported by the intramural program of the NCI. Work in the laboratory of Y.S. is supported by the A-T Medical Research Foundation, the A-T Children's Project, The Israel Science Foundation, the A-T Medical Research Trust, the Israel-Germany Joint Program on Cancer Research, and the A-T Ease Foundation.

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Author notes

  1. Frédéric Catez

    Present address: Current address: Université Lyon 1, Lyon, F-69003, France; CNRS, UMR5534, Centre de génétique moléculaire et cellulaire, Villeurbanne, F-69622, France.,

  2. Yong-Chul Kim and Gabi Gerlitz: These authors contributed equally.

Authors and Affiliations

  1. Laboratory of Metabolism,

    Yong-Chul Kim, Gabi Gerlitz, Takashi Furusawa, Frédéric Catez & Michael Bustin

  2. Experimental Immunology Branch and,

    Andre Nussenzweig

  3. Basic Research Laboratory, CCR, National Cancer Institute, National Institutes of Health, Bethesda, 20892, MD, USA

    Kyu-Seon Oh & Kenneth H. Kraemer

  4. Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, 69978, Tel Aviv, Israel

    Yosef Shiloh

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Correspondence to Michael Bustin.

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Kim, YC., Gerlitz, G., Furusawa, T. et al. Activation of ATM depends on chromatin interactions occurring before induction of DNA damage. Nat Cell Biol 11, 92–96 (2009). https://doi.org/10.1038/ncb1817

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