Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

Nature volume 452, pages 492–496 (2008)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: SIRT6 knockdown leads to premature cellular senescence and telomere dysfunction.
Figure 2: SIRT6 associates with telomeric chromatin.
Figure 3: SIRT6 deacetylates lysine 9 of histone H3 at telomeric chromatin.
Figure 4: SIRT6 stabilizes WRN at telomeric chromatin and prevents replication-associated telomere defects.

Similar content being viewed by others

References

  1. Landry, J. et al. The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases. Proc. Natl Acad. Sci. USA 97, 5807–5811 (2000)

    Article  ADS  CAS  Google Scholar 

  2. Imai, S., Armstrong, C. M., Kaeberlein, M. & Guarente, L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403, 795–800 (2000)

    Article  ADS  CAS  Google Scholar 

  3. Mostoslavsky, R. et al. Genomic instability and aging-like phenotype in the absence of mammalian SIRT6. Cell 124, 315–329 (2006)

    Article  CAS  Google Scholar 

  4. Cheng, W. H., Muftuoglu, M. & Bohr, V. A. Werner syndrome protein: Functions in the response to DNA damage and replication stress in S-phase. Exp. Gerontol. 42, 871–878 (2007)

    Article  CAS  Google Scholar 

  5. Multani, A. S. & Chang, S. WRN at telomeres: implications for aging and cancer. J. Cell Sci. 120, 713–721 (2007)

    Article  CAS  Google Scholar 

  6. Campisi, J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120, 513–522 (2005)

    Article  CAS  Google Scholar 

  7. Verdun, R. E. & Karlseder, J. Replication and protection of telomeres. Nature 447, 924–931 (2007)

    Article  ADS  CAS  Google Scholar 

  8. van Overbeek, M. & de Lange, T. Apollo, an Artemis-related nuclease, interacts with TRF2 and protects human telomeres in S phase. Curr. Biol. 16, 1295–1302 (2006)

    Article  CAS  Google Scholar 

  9. Takai, H., Smogorzewska, A. & de Lange, T. DNA damage foci at dysfunctional telomeres. Curr. Biol. 13, 1549–1556 (2003)

    Article  CAS  Google Scholar 

  10. d’Adda di Fagagna, F. et al. A DNA damage checkpoint response in telomere-initiated senescence. Nature 426, 194–198 (2003)

    Article  ADS  Google Scholar 

  11. van Steensel, B., Smogorzewska, A. & de Lange, T. TRF2 protects human telomeres from end-to-end fusions. Cell 92, 401–413 (1998)

    Article  CAS  Google Scholar 

  12. Sherr, C. J. & DePinho, R. A. Cellular senescence: mitotic clock or culture shock? Cell 102, 407–410 (2000)

    Article  CAS  Google Scholar 

  13. Crabbe, L., Verdun, R. E., Haggblom, C. I. & Karlseder, J. Defective telomere lagging strand synthesis in cells lacking WRN helicase activity. Science 306, 1951–1953 (2004)

    Article  ADS  CAS  Google Scholar 

  14. Laud, P. R. et al. Elevated telomere–telomere recombination in WRN-deficient, telomere dysfunctional cells promotes escape from senescence and engagement of the ALT pathway. Genes Dev. 19, 2560–2570 (2005)

    Article  CAS  Google Scholar 

  15. Crabbe, L., Jauch, A., Naeger, C. M., Holtgreve-Grez, H. & Karlseder, J. Telomere dysfunction as a cause of genomic instability in Werner syndrome. Proc. Natl Acad. Sci. USA 104, 2205–2210 (2007)

    Article  ADS  CAS  Google Scholar 

  16. Wyllie, F. S. et al. Telomerase prevents the accelerated cell ageing of Werner syndrome fibroblasts. Nature Genet. 24, 16–17 (2000)

    Article  CAS  Google Scholar 

  17. Opresko, P. L. et al. The Werner syndrome helicase and exonuclease cooperate to resolve telomeric D loops in a manner regulated by TRF1 and TRF2. Mol. Cell 14, 763–774 (2004)

    Article  CAS  Google Scholar 

  18. Loayza, D. & De Lange, T. POT1 as a terminal transducer of TRF1 telomere length control. Nature 423, 1013–1018 (2003)

    Article  ADS  CAS  Google Scholar 

  19. Benetti, R., Garcia-Cao, M. & Blasco, M. A. Telomere length regulates the epigenetic status of mammalian telomeres and subtelomeres. Nature Genet. 39, 243–250 (2007)

    Article  CAS  Google Scholar 

  20. Ariyoshi, K., Suzuki, K., Goto, M., Watanabe, M. & Kodama, S. Increased chromosome instability and accumulation of DNA double-strand breaks in Werner syndrome cells. J. Radiat. Res. (Tokyo) 48, 219–231 (2007)

    Article  ADS  CAS  Google Scholar 

  21. Takeuchi, F., Hanaoka, F., Goto, M., Yamada, M. & Miyamoto, T. Prolongation of S phase and whole cell cycle in Werner’s syndrome fibroblasts. Exp. Gerontol. 17, 473–480 (1982)

    Article  CAS  Google Scholar 

  22. Poot, M., Hoehn, H., Runger, T. M. & Martin, G. M. Impaired S-phase transit of Werner syndrome cells expressed in lymphoblastoid cell lines. Exp. Cell Res. 202, 267–273 (1992)

    Article  CAS  Google Scholar 

  23. Tommerup, H., Dousmanis, A. & de Lange, T. Unusual chromatin in human telomeres. Mol. Cell. Biol. 14, 5777–5785 (1994)

    Article  CAS  Google Scholar 

  24. Blasco, M. A. The epigenetic regulation of mammalian telomeres. Nature Rev. Genet. 8, 299–309 (2007)

    Article  CAS  Google Scholar 

  25. Chang, S. et al. Essential role of limiting telomeres in the pathogenesis of Werner syndrome. Nature Genet. 36, 877–882 (2004)

    Article  CAS  Google Scholar 

  26. Herbig, U., Jobling, W. A., Chen, B. P., Chen, D. J. & Sedivy, J. M. Telomere shortening triggers senescence of human cells through a pathway involving ATM, p53, and p21CIP1, but not p16INK4a. Mol. Cell 14, 501–513 (2004)

    Article  CAS  Google Scholar 

  27. Dimitrova, N. & de Lange, T. MDC1 accelerates nonhomologous end-joining of dysfunctional telomeres. Genes Dev. 20, 3238–3243 (2006)

    Article  CAS  Google Scholar 

  28. Padilla-Nash, H. M. et al. Jumping translocations are common in solid tumor cell lines and result in recurrent fusions of whole chromosome arms. Genes Chromosom. Cancer 30, 349–363 (2001)

    Article  CAS  Google Scholar 

  29. Michishita, E., Park, J. Y., Burneskis, J. M., Barrett, J. C. & Horikawa, I. Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol. Biol. Cell 16, 4623–4635 (2005)

    Article  CAS  Google Scholar 

  30. Chua, K. F. et al. Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress. Cell Metab. 2, 67–76 (2005)

    Article  CAS  Google Scholar 

  31. Dimri, G. P. et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl Acad. Sci. USA 92, 9363–9367 (1995)

    Article  ADS  CAS  Google Scholar 

  32. Schrock, E. et al. Multicolor spectral karyotyping of human chromosomes. Science 273, 494–497 (1996)

    Article  ADS  CAS  Google Scholar 

Download references

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

Author notes

  1. J. Carl Barrett

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

Authors and 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

Authors
  1. Eriko Michishita
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ronald A. McCord
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elisabeth Berber
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mitomu Kioi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hesed Padilla-Nash
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mara Damian
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Peggie Cheung
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Rika Kusumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tiara L. A. Kawahara
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. J. Carl Barrett
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Howard Y. Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Vilhelm A. Bohr
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Thomas Ried
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Or Gozani
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Katrin F. Chua
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Katrin F. Chua.

Supplementary information

Supplementary Information

The file contains Supplementary Figures 1-14 with Legends. (PDF 4713 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Michishita, E., McCord, R., Berber, E. et al. SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature 452, 492–496 (2008). https://doi.org/10.1038/nature06736

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature06736

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing