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SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin
Open accessAbstract
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.
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TL;DR
Human SIRT6 is an NAD+-dependent histone H3 lysine 9 (H3K9) deacetylase that associates with telomeres in S phase and maintains low H3K9 acetylation there. SIRT6 depletion causes telomere dysfunction, chromosomal end-to-end fusions, and premature cellular senescence, and impairs WRN association at telomeric chromatin, linking SIRT6 to telomere maintenance and Werner syndrome-like defects.
Key findings
- SIRT6 knockdown in WI-38 human fibroblasts shortened replicative lifespan, causing premature senescence about ten population doublings before controls, with increased senescence-associated β-galactosidase staining; two independent SIRT6 shRNAs reproduced this, while irrelevant shRNAs did not.
- SIRT6-depleted cells showed elevated telomere dysfunction-induced foci, non-recurrent chromosomal end-to-end fusions that were more pronounced at later population doublings, and Werner syndrome-like telomere abnormalities including sister telomere loss, telomere doublets, and weak or absent telomere signals at fusion sites; mean telomere length was not significantly reduced.
- SIRT6 deacetylated H3K9Ac specifically among tested acetylated histone peptides, with no deacetylation detected for 12 other acetylated histone peptides; the catalytic mutant H133Y markedly decreased activity. SIRT6 knockdown caused H3K9 hyperacetylation at telomeric chromatin in S phase, and S6KO mouse cells also showed telomeric H3K9 hyperacetylation.
- SIRT6 was required for stable WRN association at telomeric chromatin; SIRT6 knockdown significantly inhibited WRN association in U2OS and IMR90 cells. Telomerase expression reversed premature senescence, whereas augmenting base excision repair did not, and low oxygen culture did not prevent senescence.
Methods
- Retrovirus-mediated shRNA knockdown of SIRT6 in WI-38, IMR90, U2OS, and HeLa cells, with replicative senescence assays, SA-β-gal staining, immuno-FISH TIF assays, metaphase cytogenetics/SKY/telomere FISH, and cell-cycle flow cytometry.
- Telomere chromatin immunoprecipitation (T-ChIP) after thymidine synchronization and release, using antibodies against SIRT6, Flag, WRN, and H3K9Ac, with telomeric DNA detected by slot blot.
- In vitro histone deacetylation assays with recombinant SIRT6 and acetylated histone tail peptides or full-length histones, including mass spectrometry; 293T cells were transfected with wild-type or H133Y SIRT6 and analyzed by Western blotting.
Limitations
- Stated: SIRT6 showed only modest in vitro deacetylation activity on H3K9Ac peptides, and no direct SIRT6-WRN interaction at chromatin was observed, although additional functional or physical interactions might exist.
- Stated: S6KO mouse cells showed telomeric H3K9 hyperacetylation but did not display the downstream cellular defects seen in human cells, which the authors attribute to the large functional reserve of mouse telomeres.
- Evident: many conclusions rely on shRNA knockdown and overexpression in cultured cells, and several supporting results are reported as “data not shown”; global H3K9Ac levels did not differ significantly, so the key effect is telomere-specific.
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“As controls, the association of Alu repeat sequences with SIRT6 ChIPs was not above background (Fig. 2b–d), and the SIRT6 T-ChIP signal was abolished in S6KD cells, validating the specificity of the signal (Fig. 2d).”
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“In both U2OS and IMR90 cells, SIRT6 knockdown significantly inhibited the association of WRN with telomeric chromatin (Fig. 4a, b, and data not shown).”
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“However, mean telomere length was not significantly reduced in S6KD cells (Supplementary Fig. 5).”
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“Inactivation of SIRT6 leads to H3K9 hyperacetylation at telomeric chromatin in both human and mouse cells, but the mouse cells do not display the downstream cellular defects observed in human cells, which is consistent with the large functional reserve of mouse telomeres (Supplementary Fig. 13d; data not shown)14,25.”
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“First, telomere stabilization (by the ectopic expression of telomerase (hTERT)) reversed the premature senescence of S6KD, whereas augmenting BER (by the ectopic expression of the DNA polymerase-β dRP lyase domain) did not (Fig. 1g and Supplementary Fig. 6).”
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“Inactivation of SIRT6 leads to H3K9 hyperacetylation at telomeric chromatin in both human and mouse cells, but the mouse cells do not display the downstream cellular defects observed in human cells, which is consistent with the large functional reserve of mouse telomeres (Supplementary Fig. 13d; data not shown)14,25.”
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“First, telomere stabilization (by the ectopic expression of telomerase (hTERT)) reversed the premature senescence of S6KD, whereas augmenting BER (by the ectopic expression of the DNA polymerase-β dRP lyase domain) did not (Fig. 1g and Supplementary Fig. 6).”
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“Analysis of TIFs revealed elevated telomere dysfunction in S6KD cells (Fig. 1d, e, and Supplementary Fig. 4a).”
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“Similarly, SIRT6 knockdown in U2OS cells resulted in delayed completion of S phase (Supplementary Fig. 14), which is consistent with a role for SIRT6 in modulating telomeres during replication.”
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“In contrast, investigation of histone acetylation status at telomeres in S-phase-enriched cultures by T-ChIP revealed H3K9 hyperacetylation in S6KD cells (Fig. 3d–f).”
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“Premature cellular senescence was also observed with two independent SIRT6 shRNAs, ruling out off-target shRNA effects, but not with irrelevant shRNAs (Supplementary Fig 2b–d and Supplementary Fig 3c).”
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“SIRT6 occupancy at telomeric chromatin was observed for both recombinant Flag-tagged SIRT6 (Fig. 2a, b) and endogenous SIRT6 (Fig. 2c, d), and in both U2OS osteosarcoma cells (Fig. 2b, c) and primary IMR90 cells (Fig. 2d).”
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“This activity was highly specific for H3K9Ac, because no deacetylation was detected for 12 other acetylated histone peptides (Fig. 3a and Supplementary Fig. 11).”
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“SIRT6 also deacetylated H3K9Ac, but not several other acetylated residues, in the context of purified full-length histone H3, and mutation of a conserved catalytic residue (H133Y) of SIRT6 markedly decreased this activity (Fig. 3b and data not shown).”
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“SIRT6 knockdown (S6KD) cells have a strikingly shortened replicative lifespan, undergoing premature cellular senescence about ten population doublings before control cells, and show increased levels of senescence-associated β-galactosidase (SA-β-gal) staining (Fig. 1b, c, and Supplementary Fig. 2a).”
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“Finally, SIRT6 efficiently and specifically deacetylated H3K9Ac (but not other acetylated histone residues) in 293T cells, whereas the mutant SIRT6 protein did not (Fig. 3c and Supplementary Fig. 12).”
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“Non-recurrent chromosomal end-to-end fusions were observed in S6KD cells and were more pronounced at later population doublings, but they were rarely observed in control cells (Fig. 1f and Supplementary Fig. 4b, c).”
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“First, S6KD metaphases showed elevated levels of missing telomere signals (sister telomere loss) and extra telomere signals (telomere doublets) (Fig. 4d–f), defects observed in WS cells and associated with aberrant telomere processing during replication8,13,20.”
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“Together, these observations suggest that S6KD cells undergo accelerated senescence and telomere dysfunction in response to stochastic telomere sequence loss, without increased global telomere erosion.”
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“We conclude that SIRT6 is crucial in maintaining a normal replicative life-span and in preventing the premature senescence of human cells.”
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“Together, these data locate SIRT6 at telomeric chromatin in S phase and suggest a potential role for SIRT6 in regulating replication-associated dynamics in telomere structure.”
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“Together, these findings suggest that SIRT6 collaborates with WRN at telomeric chromatin to ensure efficient telomere replication and to prevent the accrual of structural abnormalities at telomeres.”
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“Our study has identified a crucial function for SIRT6 in chromatin regulation at mammalian telomeres and provides a new mechanism by which the regulation of chromatin is linked to telomere function, cellular senescence and, potentially, organismal ageing.”
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“Together, these observations indicate that SIRT6 is an NAD-dependent deacetylase with specificity for H3K9Ac.”
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“We propose a model (Supplementary Fig. 1) in which the deacetylation of H3K9Ac by SIRT6 promotes the formation of a specialized telomeric chromatin state that is required for the stable association of S-phase-dependent telomere-processing factors such as WRN, to prevent aberrant sequence loss or metabolism of telomeres.”
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“Together, these findings demonstrate that telomere dysfunction, not BER defects or oxidative stress, underlie the premature senescence phenotype of S6KD cells.”
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“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.”
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“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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The paper relies on this without support.
No enzymatic activity of SIRT6 at chromatin has yet been detected, and the identity of physiological SIRT6 substrates is unknown.
“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.”
“Although no physiological enzymatic activity for SIRT6 on histones or other trans substrate has yet been observed, we proposed that SIRT6 might regulate chromatin at telomeres by deacetylating a specific histone tail residue.”
The paper relies on this without support.
No effect of SIRT6 deficiency on cellular lifespan has been reported.
“Despite the ageing-like phenotype of SIRT6-deficient mice, no effect of SIRT6 deficiency on cellular lifespan has been reported.”
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“SIRT6 promotes DNA double strand break repair19,20, regulates telomere stability21, suppresses inflammation22 and opposes tumorigenesis23,24.”
From SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age (2014) · cites this paper as [21]
In the citing paper
“In human cells, loss of SIRT6, an H3K9 deacetylase that silences telomeres, causes telomere dysfunction and premature cellular senescence (Michishita et al., 2008).”
From The Aging Epigenome (2016) · cites this paper as Michishita et al., 2008
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Metadata
- Authors
- Michishita, E., McCord, R. A., Berber, E., Kioi, M., Padilla-Nash, H., Damian, M., Cheung, P., Kusumoto, R., Kawahara, T. L. A., Barrett, J. C., Chang, H. Y., Bohr, V. A., Ried, T., Gozani, O., & Chua, K. F.
- Affiliations
- Stanford Medicine (US)
- VA Palo Alto Health Care System (US)
- Department of Biological Sciences (RU)
- National Institutes of Health (US)
- Corresponding author
- Chua, Katrin F.
- ORCID
- Venue
- Nature
- Published
- 2008-03
- Volume
- 452
- Issue
- 7186
- Pages
- 492-496
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2646112
- OpenAlex
- W2029969982
- Semantic Scholar
- e93e298451cb0d965e8933da9a3ab04e44f65ff0
- Cited by
- 1,111
- References
- 32
- Citations by year
- 2026: 35 · 2025: 35 · 2024: 45 · 2023: 59 · 2022: 57 · 2021: 68 · 2020: 75 · 2019: 64 · 2018: 75 · 2017: 63 · 2016: 83 · 2015: 68 · 2014: 62 · 2013: 94 · 2012: 57
- FWCI
- 23.11
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute on Aging (R01AG028867, K08AG028961)
- National Institute of General Medical Sciences (R01GM079641)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- SIRT6, telomeric chromatin, telomere maintenance, premature aging, Werner syndrome, WRN, cellular senescence, chromatin silencing, telomere dysfunction, NAD+-dependent deacetylation
- MeSH terms
- Werner Syndrome Helicase, Acetylation, Cell Line, Chromatin, DNA Replication, Exodeoxyribonucleases, Fibroblasts, Histone Deacetylases, Histones, Humans, Lysine, Phenotype, Protein Binding, Werner Syndrome, Telomere, Cellular Senescence, Telomerase, Sirtuins, RecQ Helicases
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