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Phosphorylation of histone H3 Ser10 establishes a hierarchy for subsequent intramolecular modification events

Nature Structural & Molecular Biology volume 19, pages 819–823 (2012)Cite this article

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Abstract

Phosphorylation of Ser10 of histone H3 regulates chromosome condensation and transcriptional activity. Using time-resolved, high-resolution NMR spectroscopy, we demonstrate that histone H3 Ser10 phosphorylation inhibits checkpoint kinase 1 (Chk1)– and protein kinase C (PKC)–mediated modification of Thr11 and Thr6, the respective primary substrate sites of these kinases. On unmodified H3, both enzymes also target Ser10 and thereby establish autoinhibitory feedback states on individual H3 tails. Whereas phosphorylated Ser10 does not affect acetylation of Lys14 by Gcn5, phosphorylated Thr11 impedes acetylation. Our observations reveal mechanistic hierarchies of H3 phosphorylation and acetylation events and provide a framework for intramolecular modification cross-talk within the N terminus of histone H3.

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Figure 1: Mutually exclusive phosphorylation of H3 Thr11 and Ser10 by Chk1.
Figure 2: Nonreciprocal Ser10 phosphorylation hierarchies.
Figure 3: Mutually exclusive phosphorylation of H3 Thr6 (pThr6) and Ser10 by PKCα.
Figure 4: H3 Thr11 phosphorylation impedes Lys14 acetylation by Gcn5.

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Acknowledgements

We thank P. Schmieder and M. Beerbaum for excellent NMR infrastructure maintenance. A.S. and W.F. acknowledge funding by the Max Planck Gesellschaft (MBG). S.J.E. was supported by a Boehringer Ingelheim Fund (BIF) fellowship. F.-X.T. acknowledges support from the Association pour la Recherche contre le Cancer (ARC). D.S. and P.S. are supported by Emmy Noether research grants (SCHW1163/3-1 and SE1794/1-1) from the Deutsche Forschungsgemeinschaft (DFG).

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  1. Simon J Elsässer & Dirk Schwarzer

    Present address: Present addresses: MRC Laboratory of Molecular Biology, Cambridge, UK (S.J.E.); Interfaculty Institute of Biochemistry (IFIB), University of Tübingen, Tübingen, Germany (D.S.).,

Authors and Affiliations

  1. Department of NMR-supported Structural Biology, Leibniz Institute of Molecular Pharmacology (FMP Berlin), Berlin, Germany

    Stamatios Liokatis, Francois-Xavier Theillet, Barth van Rossum & Philipp Selenko

  2. Laboratory of Chromatin Biochemistry, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany

    Alexandra Stützer & Wolfgang Fischle

  3. Laboratory of Chromatin Biology and Epigenetics, Rockefeller University, New York, New York, USA

    Simon J Elsässer & C David Allis

  4. Department of Chemical Biology, Leibniz Institute of Molecular Pharmacology (FMP Berlin), Berlin, Germany

    Rebecca Klingberg & Dirk Schwarzer

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Contributions

S.L. conceived and performed NMR and biochemical experiments, analyzed the data and wrote the paper. A.S. and S.J.E. conceived and performed biochemical experiments. F.-X.T. performed computational modeling. R.K. performed peptide synthesis. B.v.R. performed structural modeling and visualization. D.S., C.D.A. and W.F. conceived biochemical experiments, discussed data and wrote parts of the manuscript. P.S. developed the project, supervised all experiments, analyzed the data, wrote the manuscript and made the figures. All authors discussed ideas and concepts, carefully read the manuscript and approved of the conclusions drawn therein.

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Correspondence to Philipp Selenko.

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Liokatis, S., Stützer, A., Elsässer, S. et al. Phosphorylation of histone H3 Ser10 establishes a hierarchy for subsequent intramolecular modification events. Nat Struct Mol Biol 19, 819–823 (2012). https://doi.org/10.1038/nsmb.2310

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