title: SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin.
abstract: The Sir2 deacetylase regulates chromatin silencing and lifespan in Saccharomyces cerevisiae. In mice, deficiency for the Sir2 family member SIRT6 leads to a shortened lifespan and a premature ageing-like phenotype. However, the molecular mechanisms of SIRT6 function are unclear. SIRT6 is a chromatin-associated protein, 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. At telomeric chromatin, SIRT6 deacetylates H3K9 and is required for the stable association of WRN, the factor that is mutated in Werner syndrome. 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.
authors.affiliation: Department of Medicine, Division of Endocrinology, Gerontology and Metabolism, School of Medicine, Stanford University, Stanford, California 94305, USA.
authors.forename: Eriko
authors.initials: E
authors.lastname: Michishita
authors.forename: Ronald A
authors.initials: RA
authors.lastname: McCord
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Berber
authors.forename: Mitomu
authors.initials: M
authors.lastname: Kioi
authors.forename: Hesed
authors.initials: H
authors.lastname: Padilla-Nash
authors.forename: Mara
authors.initials: M
authors.lastname: Damian
authors.forename: Peggie
authors.initials: P
authors.lastname: Cheung
authors.forename: Rika
authors.initials: R
authors.lastname: Kusumoto
authors.forename: Tiara L A
authors.initials: TL
authors.lastname: Kawahara
authors.forename: J Carl
authors.initials: JC
authors.lastname: Barrett
authors.forename: Howard Y
authors.initials: HY
authors.lastname: Chang
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
authors.forename: Thomas
authors.initials: T
authors.lastname: Ried
authors.forename: Or
authors.initials: O
authors.lastname: Gozani
authors.forename: Katrin F
authors.initials: KF
authors.lastname: Chua
mesh_terms: D000107:Acetylation; D002460:Cell Line; D016922:Cellular Senescence / Q000235:genetics; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication; D005090:Exodeoxyribonucleases / Q000378:metabolism; D005347:Fibroblasts; D006655:Histone Deacetylases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding; D053484:RecQ Helicases / Q000378:metabolism; D037761:Sirtuins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000235:genetics / Q000378:metabolism*; D014898:Werner Syndrome / Q000235:genetics; D000071657:Werner Syndrome Helicase
chemical_list: D002843:Chromatin; D006657:Histones; D019098:Telomerase; D005090:Exodeoxyribonucleases; C516592:SIRT6 protein, human; D037761:Sirtuins; D006655:Histone Deacetylases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase; D008239:Lysine