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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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29 Own result · 23 Own interpretation · 3 Not checked yet · 1 Own method · 1 No basis given
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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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“SIRT6 manifested modest deacetylation activity on peptides containing acetylated H3K9 (H3K9Ac) (Fig. 3a and Supplementary Fig. 10).”
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“The telomere signals at TIFs in S6KD cells are weak compared with non-TIF telomere signals, suggesting a subpopulation of telomeres that have undergone significant sequence loss (see below).”
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“SIRT6 associates specifically with telomeres, and SIRT6 depletion leads to telomere dysfunction with end-to-end chromosomal fusions and premature cellular senescence.”
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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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“H3K9 was also hyperacetylated at telomeric chromatin in S6KO mouse cells, providing in vivo evidence for a physiological role for SIRT6 in deacetylating this histone residue (Supplementary Fig. 13a–c).”
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“Second, S6KD cells underwent premature senescence even when cultured under low (physiological) oxygen conditions (Supplementary Fig. 7).”
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“However, the association of SIRT6 with telomeres was independent of WRN (Supplementary Fig. 13e), and we have not observed a direct interaction between SIRT6 and WRN at chromatin (data not shown).”
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“T-ChIP analysis at different time points after release from cell synchronization revealed that SIRT6, like WRN, preferentially associates with telomeric chromatin in S-phase-enriched cultures (Supplementary Fig. 9).”
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“Here we show that the human SIRT6 protein is an NAD+-dependent, histone H3 lysine 9 (H3K9) deacetylase that modulates telomeric chromatin.”
- Also stated in: § Abstract · hedged
“Together, these observations indicate that SIRT6 is an NAD-dependent deacetylase with specificity for H3K9Ac.”
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“In addition, chromosome fusions in S6KD cells, as in WRN-defective cells14,15, have weak or no telomere signals at the fusion sites (Fig. 4c).”
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“Western analysis of S6KD and control cells did not reveal significant differences in global H3K9Ac levels (data not shown).”
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“However, the association of SIRT6 with telomeres was independent of WRN (Supplementary Fig. 13e), and we have not observed a direct interaction between SIRT6 and WRN at chromatin (data not shown).”
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“The resulting telomere dysfunction then contributes to premature cellular senescence.”
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“We conclude that SIRT6 is required for stabilization of WRN at telomeric chromatin.”
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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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“Here we show that the human SIRT6 protein is an NAD+-dependent, histone H3 lysine 9 (H3K9) deacetylase that modulates telomeric chromatin.”
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“SIRT6 is therefore required for the maintenance of the low physiological levels of H3K9 acetylation at telomeric chromatin in S phase, and hyperacetylation of H3K9 in the absence of SIRT6 correlates with telomere dysfunction.”
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“H3K9 was also hyperacetylated at telomeric chromatin in S6KO mouse cells, providing in vivo evidence for a physiological role for SIRT6 in deacetylating this histone residue (Supplementary Fig. 13a–c).”
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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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“The telomere signals at TIFs in S6KD cells are weak compared with non-TIF telomere signals, suggesting a subpopulation of telomeres that have undergone significant sequence loss (see below).”
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“SIRT6 is therefore required for the maintenance of the low physiological levels of H3K9 acetylation at telomeric chromatin in S phase, and hyperacetylation of H3K9 in the absence of SIRT6 correlates with telomere dysfunction.”
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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.”
What the sources say
- Not checked yetcites [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) source
- Not checked yetcites [25] Chang, S. et al. Essential role of limiting telomeres in the pathogenesis of Werner syndrome. Nature Genet. 36, 877–882 (2004) source
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“These observations indicate that SIRT6 is critical for maintaining functional telomeres to avert chromosomal instability due to aberrant chromosomal end-to-end fusions.”
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“Moreover, SIRT6-depleted cells exhibit abnormal telomere structures that resemble defects observed in Werner syndrome, a premature ageing disorder4,5.”
What the sources say
- Not checked yetcites [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) source
- Not checked yetcites [5] Multani, A. S. & Chang, S. WRN at telomeres: implications for aging and cancer. J. Cell Sci. 120, 713–721 (2007) source
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“Our results indicate that deacetylation of H3K9Ac by SIRT6 is important during S phase at replicating telomeres.”
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“Thus, our data are consistent with the hypothesis that SIRT6 deacetylation of H3K9Ac at telomeric chromatin leads to an altered chromatin state that is required for efficient WRN association in S phase.”
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“In this study we show that human SIRT6 deacetylates H3K9Ac at telomeres to prevent telomere dysfunction.”
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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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- Rests on an assumption: No enzymatic activity of SIRT6 at chromatin has yet been detected, and the identity of physiological SIRT6 substrates is unknown.
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In the paper
“At telomeric chromatin, SIRT6 deacetylates H3K9 and is required for the stable association of WRN, the factor that is mutated in Werner syndrome4,5.”
What the sources say
- Not checked yetcites [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) source
- Not checked yetcites [5] Multani, A. S. & Chang, S. WRN at telomeres: implications for aging and cancer. J. Cell Sci. 120, 713–721 (2007) source
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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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In the paper
“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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In the paper
“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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In the paper
“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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In the paper
“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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In the paper
“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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In the paper
“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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In the paper
“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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In the paper
“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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In the paper
“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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In the paper
“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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In the paper
“Together, these observations indicate that SIRT6 is an NAD-dependent deacetylase with specificity for H3K9Ac.”
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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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In the paper
“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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In the paper
“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.”
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“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.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“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
Citations
Cites
A biomarker that identifies senescent human cells in culture and in aging skin in vivo.
Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E. E., Linskens, M., Rubelj, I., & Pereira-Smith, O. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.20.9363 · Cited by 7,477
Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase
Imai, S.-I., Armstrong, C. M., Kaeberlein, M., & Guarente, L. (2000) · Nature · doi:10.1038/35001622 · Cited by 3,510
A DNA damage checkpoint response in telomere-initiated senescence
Fagagna, F. D. D., Reaper, P. M., Clay-Farrace, L., Fiegler, H., Carr, P., von Zglinicki, T., Saretzki, G., Carter, N. P., & Jackson, S. P. (2003) · Nature · doi:10.1038/nature02118 · Cited by 2,917
Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors
Campisi, J. (2005) · Cell · doi:10.1016/j.cell.2005.02.003 · Cited by 2,379
Multicolor Spectral Karyotyping of Human Chromosomes
Schröck, E., du Manoir, S., Veldman, T., Schoell, B., Wienberg, J., Ferguson-Smith, M. A., Ning, Y., Ledbetter, D. H., Bar‐Am, I., Soenksen, D. G., et al. (1996) · Science · doi:10.1126/science.273.5274.494 · Cited by 1,753
Self-citationTRF2 Protects Human Telomeres from End-to-End Fusions
van Steensel, B., Smogorzewska, A., & de Lange, T. (1998) · Cell · doi:10.1016/s0092-8674(00)80932-0 · Cited by 1,709
Genomic Instability and Aging-like Phenotype in the Absence of Mammalian SIRT6
Mostoslavsky, R., Chua, K. F., Lombard, D. B., Pang, W. W., Fischer, M. R., Gellon, L., Liu, P., Mostoslavsky, G., Franco, S., Murphy, M. M., et al. (2006) · Cell · doi:10.1016/j.cell.2005.11.044 · Cited by 1,637
Self-citationDNA Damage Foci at Dysfunctional Telomeres
Takai, H., Smogorzewska, A., & de Lange, T. (2003) · Current Biology · doi:10.1016/s0960-9822(03)00542-6 · Cited by 1,409
Michishita, E., Park, J. Y., Burneskis, J. M., Barrett, J. C., & Horikawa, I. (2005) · Molecular Biology of the Cell · doi:10.1091/mbc.e05-01-0033 · Cited by 1,364
Self-citationHerbig, U., Jobling, W. A., Chen, B. P. C., Chen, D. J., & Sedivy, J. M. (2004) · Molecular Cell · doi:10.1016/s1097-2765(04)00256-4 · Cited by 1,344
Cited by
Sorted by citations
Mammalian Sirtuins: Biological Insights and Disease Relevance
Haigis, M. C., & Sinclair, D. A. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev.pathol.4.110807.092250 · Cited by 2,085
Erasers of Histone Acetylation: The Histone Deacetylase EnzymesPreprint
Seto, E., & Yoshida, M. (2014) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a018713 · Cited by 2,105
Sirtuins as regulators of metabolism and healthspan
Houtkooper, R. H., Pirinen, E., & Auwerx, J. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3293 · Cited by 2,008
Recent progress in the biology and physiology of sirtuins
Finkel, T., Deng, C., & Mostoslavsky, R. (2009) · Nature · doi:10.1038/nature08197 · Cited by 1,506
Sirt5 Is a NAD-Dependent Protein Lysine Demalonylase and Desuccinylase
Du, J., Zhou, Y., Su, X., Yu, J. J., Khan, S., Jiang, H., Kim, J., Woo, J., Kim, J. H., Choi, B. H., et al. (2011) · Science · doi:10.1126/science.1207861 · Cited by 1,429
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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