SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin.
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.
Michishita
Eriko
E
Department of Medicine, Division of Endocrinology, Gerontology and Metabolism, School of Medicine, Stanford University, Stanford, California 94305, USA.
McCord
Ronald A
RA
Berber
Elisabeth
E
Kioi
Mitomu
M
Padilla-Nash
Hesed
H
Damian
Mara
M
Cheung
Peggie
P
Kusumoto
Rika
R
Kawahara
Tiara L A
TL
Barrett
J Carl
JC
Chang
Howard Y
HY
Bohr
Vilhelm A
VA
Ried
Thomas
T
Gozani
Or
O
Chua
Katrin F
KF
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
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