1. Department of Medicine, Division of Endocrinology, Gerontology and Metabolism, School of Medicine,
2. Department of Radiation Oncology, School of Medicine,
3. Department of Biological Sciences, and,
4. Program in Epithelial Biology, School of Medicine, Stanford University, Stanford, California 94305, USA
5. Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System, Palo Alto, California 94304, USA
6. Genetics Branch, and,
7. Laboratory of Biosystems and Cancer, Center for Cancer Research, National Cancer Institute/NIH, Bethesda, Maryland 20892, USA
8. Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, Maryland 21224, USA
9. Present address: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA.

Correspondence to: Katrin F. Chua^1,5 Correspondence and requests for materials should be addressed to K.F.C. (Email: kfchua@stanford.edu).

Abstract

The Sir2 deacetylase regulates chromatin silencing and lifespan in Saccharomyces cerevisiae^{1, 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 disorder^{4, 5}. At telomeric chromatin, SIRT6 deacetylates H3K9 and is required for the stable association of WRN, the factor that is mutated in Werner syndrome^{4, 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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