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SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin

Nature 452, 492–496 (27 March 2008) | Download Citation

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Abstract

The Sir2 deacetylase regulates chromatin silencing and lifespan in Saccharomyces cerevisiae1,2. In mice, deficiency for the Sir2 family member SIRT6 leads to a shortened lifespan and a premature ageing-like phenotype3. However, the molecular mechanisms of SIRT6 function are unclear. SIRT6 is a chromatin-associated protein3, but no enzymatic activity of SIRT6 at chromatin has yet been detected, and the identity of physiological SIRT6 substrates is unknown. Here we show that the human SIRT6 protein is an NAD+-dependent, histone H3 lysine 9 (H3K9) deacetylase that modulates telomeric chromatin. SIRT6 associates specifically with telomeres, and SIRT6 depletion leads to telomere dysfunction with end-to-end chromosomal fusions and premature cellular senescence. Moreover, SIRT6-depleted cells exhibit abnormal telomere structures that resemble defects observed in Werner syndrome, a premature ageing disorder4,5. At telomeric chromatin, SIRT6 deacetylates H3K9 and is required for the stable association of WRN, the factor that is mutated in Werner syndrome4,5. We propose that SIRT6 contributes to the propagation of a specialized chromatin state at mammalian telomeres, which in turn is required for proper telomere metabolism and function. Our findings constitute the first identification of a physiological enzymatic activity of SIRT6, and link chromatin regulation by SIRT6 to telomere maintenance and a human premature ageing syndrome.

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Acknowledgements

We thank S. Artandi, J. Karlseder, B. North, E. Verdin, J. Lipsick, H. Wen, L. Christensen and Chua and Gozani laboratory members for reagents, technical assistance and/or advice; and Regeneron Pharmaceuticals for SIRT6 knockout mice. This work was supported by grants from the National Institutes of Health (NIH) (to K.F.C., O.G., H.Y.C., R.A.M. and T.L.A.K.), the American Federation for Aging Research/Paul Beeson Scholar Award and the Department of Veterans Affairs Merit Review (to K.F.C.) and the Burroughs Wellcome Fund and Searle Scholar Award (to O.G.), and by funds from the Intramural Research Program of the NIH, the National Cancer Institute, the Center for Cancer Research and the National Institutes on Aging.

Author Contributions E.M. and R.A.M. contributed independently to this work. E.M. discovered and analysed the cellular senescence, telomere dysfunction, and S-phase defects in S6KD cells, association of SIRT6 with telomeric chromatin, and the effects of SIRT6 on H3K9Ac and WRN levels at telomeres. R.A.M. and O.G. contributed to the identification of H3K9Ac as a SIRT6 substrate. H.P.-N. and T.R. contributed to cytogenetic analysis of chromosomal fusions. E.B., M.D., M.K., P.C., R.K., V.B., J.C.B., T.L.A.K. and H.C. provided experimental assistance and reagents. E.M. and K.F.C. prepared the manuscript.

Author information

    • J. Carl Barrett

    Present address: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA.

Affiliations

  1. Department of Medicine, Division of Endocrinology, Gerontology and Metabolism, School of Medicine,

    • Eriko Michishita
    • , Ronald A. McCord
    • , Elisabeth Berber
    • , Mara Damian
    •  & Katrin F. Chua

  2. Department of Radiation Oncology, School of Medicine,

    • Mitomu Kioi

  3. Department of Biological Sciences, and,

    • Peggie Cheung
    •  & Or Gozani

  4. Program in Epithelial Biology, School of Medicine, Stanford University, Stanford, California 94305, USA

    • Tiara L. A. Kawahara
    •  & Howard Y. Chang

  5. Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, California 94304, USA

    • Eriko Michishita
    • , Ronald A. McCord
    • , Elisabeth Berber
    • , Mara Damian
    •  & Katrin F. Chua

  6. Genetics Branch, and,

    • Hesed Padilla-Nash
    •  & Thomas Ried

  7. Laboratory of Biosystems and Cancer, Center for Cancer Research, National Cancer Institute/NIH, Bethesda, Maryland 20892, USA

    • J. Carl Barrett

  8. Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, Maryland 21224, USA

    • Rika Kusumoto
    •  & Vilhelm A. Bohr

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Corresponding author

Correspondence to Katrin F. Chua.

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https://doi.org/10.1038/nature06736

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