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.
Verified 2026-10-06 · 1 reference not checked yet
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Written from the paper’s full text.
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.
Model-written summary. Check it against the paper before relying on it.
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- Findingown data§ Abstract
The association of Alu repeat sequences with SIRT6 ChIPs was not above background.
“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).”
Quote in the paperSubstantial claim - Findingown data§ Abstract
SIRT6 knockdown significantly inhibited the association of WRN with telomeric chromatin in both U2OS and IMR90 cells.
“In both U2OS and IMR90 cells, SIRT6 knockdown significantly inhibited the association of WRN with telomeric chromatin (Fig. 4a, b, and data not shown).”
Quote in the paperSubstantial claim - Findingown data§ Abstract
Mean telomere length was not significantly reduced in S6KD cells.
“However, mean telomere length was not significantly reduced in S6KD cells (Supplementary Fig. 5).”
Quote in the paperSubstantial claim - Findingown data§ Abstract
Inactivation of SIRT6 leads to H3K9 hyperacetylation at telomeric chromatin in both human and mouse cells.
“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.”
Quote in the paperSubstantial claim - Findingown data§ Abstract
Augmenting BER by ectopic expression of the DNA polymerase-β dRP lyase domain did not reverse the premature senescence of S6KD cells.
“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).”
Quote in the paperSubstantial claim
- Findingreasoning§ Abstract
Mouse cells with SIRT6 inactivation do not display the downstream cellular defects observed in human cells.
“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.”
Quote in the paperSubstantial claim - Findingown data§ Abstract
Telomere stabilization by ectopic expression of telomerase (hTERT) reversed the premature senescence of S6KD cells.
“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).”
Quote in the paperSubstantial claim - Findingown data§ Abstract
Analysis of TIFs revealed elevated telomere dysfunction in S6KD cells.
“Analysis of TIFs revealed elevated telomere dysfunction in S6KD cells (Fig. 1d, e, and Supplementary Fig. 4a).”
Quote in the paperSubstantial claim - Findingown data§ Abstract
SIRT6 knockdown in U2OS cells resulted in delayed completion of S phase.
“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.”
Quote in the paperSubstantial claim - Findingown data§ Abstract
Investigation of histone acetylation status at telomeres in S-phase-enriched cultures by T-ChIP revealed H3K9 hyperacetylation in S6KD cells.
“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).”
Quote in the paperSubstantial claim - Findingown data§ Abstract
SIRT6 manifested modest deacetylation activity on peptides containing acetylated H3K9 (H3K9Ac).
“SIRT6 manifested modest deacetylation activity on peptides containing acetylated H3K9 (H3K9Ac) (Fig. 3a and Supplementary Fig. 10).”
Quote in the paperSubstantial claim - Findingown data§ Abstract
Telomere signals at TIFs in S6KD cells are weak compared with non-TIF telomere signals.
“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).”
Quote in the paperSubstantial claim - Findingown data§ Abstract
SIRT6 associates specifically with telomeres.
“SIRT6 associates specifically with telomeres, and SIRT6 depletion leads to telomere dysfunction with end-to-end chromosomal fusions and premature cellular senescence.”
Quote in the paperSubstantial claim - Findingown data§ Abstract
S6KD cells show increased levels of senescence-associated β-galactosidase (SA-β-gal) staining.
“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).”
Quote in the paperSubstantial claim - Findingown data§ Abstract
H3K9 was hyperacetylated at telomeric chromatin in S6KO mouse cells.
“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).”
Quote in the paperSubstantial claim - Findingown data§ Abstract
S6KD cells underwent premature senescence even when cultured under low (physiological) oxygen conditions.
“Second, S6KD cells underwent premature senescence even when cultured under low (physiological) oxygen conditions (Supplementary Fig. 7).”
Quote in the paperSubstantial claim - Findingown data§ Abstract
No direct interaction between SIRT6 and WRN at chromatin was observed.
“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).”
Quote in the paperSubstantial claim - Findingown data§ Abstract
SIRT6 preferentially associates with telomeric chromatin in S-phase-enriched cultures.
“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).”
Quote in the paperSubstantial claim - Findingown data§ Abstract
Human SIRT6 is an NAD+-dependent histone H3 lysine 9 (H3K9) deacetylase.
“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.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · hedged
- Findingown data§ Abstract
Chromosome fusions in S6KD cells, as in WRN-defective cells, have weak or no telomere signals at the fusion sites.
“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).”
Quote in the paperSubstantial claim - Findingown data§ Abstract
Western analysis of S6KD and control cells did not reveal significant differences in global H3K9Ac levels.
“Western analysis of S6KD and control cells did not reveal significant differences in global H3K9Ac levels (data not shown).”
Quote in the paperSubstantial claim - Findingown data§ Abstract
The association of SIRT6 with telomeres was independent of WRN.
“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).”
Quote in the paperSubstantial claim - Interpretationown data§ Abstract
The resulting telomere dysfunction contributes to premature cellular senescence.
“The resulting telomere dysfunction then contributes to premature cellular senescence.”
Quote in the paperSubstantial claim - Interpretationown data§ Abstract
SIRT6 is required for stabilization of WRN at telomeric chromatin.
“We conclude that SIRT6 is required for stabilization of WRN at telomeric chromatin.”
Quote in the paperSubstantial claim - Study design and conductown data§ Abstract
The SIRT6 T-ChIP signal was abolished in S6KD cells, validating the specificity of the signal.
“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).”
Quote in the paperSubstantial claim - Interpretationown data§ Abstract
SIRT6 modulates telomeric chromatin.
“Here we show that the human SIRT6 protein is an NAD+-dependent, histone H3 lysine 9 (H3K9) deacetylase that modulates telomeric chromatin.”
Quote in the paperSubstantial claim - Interpretationown data§ Abstract
SIRT6 is required for the maintenance of low physiological levels of H3K9 acetylation at telomeric chromatin in S phase.
“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.”
Quote in the paperSubstantial claim - Interpretationown data§ Abstract
SIRT6 has a physiological role in deacetylating H3K9 at telomeric chromatin.
“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).”
Quote in the paperSubstantial claim - Interpretationown data§ Abstract
SIRT6 has a crucial function in chromatin regulation at mammalian telomeres.
“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.”
Quote in the paperSubstantial claim - Interpretationreasoning§ Abstract
A subpopulation of telomeres in S6KD cells has undergone significant sequence loss.
“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).”
Quote in the paperSubstantial claim - Interpretationown data§ Abstract
Hyperacetylation of H3K9 in the absence of SIRT6 correlates with telomere dysfunction.
“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.”
Quote in the paperSubstantial claim - Interpretationcitation§ Abstract
The lack of downstream cellular defects in mouse cells is consistent with the large functional reserve of mouse telomeres.
“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.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [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 in the free run.
- cites [25] Chang, S. et al. Essential role of limiting telomeres in the pathogenesis of Werner syndrome. Nature Genet. 36, 877–882 (2004) source
Not checked in the free run.
- Interpretationown data§ Abstract
SIRT6 is critical for maintaining functional telomeres to avert chromosomal instability due to aberrant chromosomal end-to-end fusions.
“These observations indicate that SIRT6 is critical for maintaining functional telomeres to avert chromosomal instability due to aberrant chromosomal end-to-end fusions.”
Quote in the paperSubstantial claim - Interpretationown data§ Abstract
SIRT6-depleted cells exhibit abnormal telomere structures that resemble defects observed in Werner syndrome.
“Moreover, SIRT6-depleted cells exhibit abnormal telomere structures that resemble defects observed in Werner syndrome, a premature ageing disorder4,5.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [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 in the free run.
- cites [5] Multani, A. S. & Chang, S. WRN at telomeres: implications for aging and cancer. J. Cell Sci. 120, 713–721 (2007) source
Not checked in the free run.
- Interpretationown data§ Abstract
Deacetylation of H3K9Ac by SIRT6 is important during S phase at replicating telomeres.
“Our results indicate that deacetylation of H3K9Ac by SIRT6 is important during S phase at replicating telomeres.”
Quote in the paperSubstantial claim - Interpretationown data§ Abstract
The 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.
“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.”
Quote in the paperSubstantial claim - Interpretationown data§ Abstract
Human SIRT6 deacetylates H3K9Ac at telomeres to prevent telomere dysfunction.
“In this study we show that human SIRT6 deacetylates H3K9Ac at telomeres to prevent telomere dysfunction.”
Quote in the paperSubstantial claim - Interpretationown data§ Abstract
The findings constitute the first identification of a physiological enzymatic activity of SIRT6.
“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.”
Quote in the paperSubstantial claim- Rests on an assumption: No enzymatic activity of SIRT6 at chromatin has yet been detected, and the identity of physiological SIRT6 substrates is unknown.
- Interpretationown data§ Abstract
SIRT6 is required for the stable association of WRN, the factor mutated in Werner syndrome, at telomeric chromatin.
“At telomeric chromatin, SIRT6 deacetylates H3K9 and is required for the stable association of WRN, the factor that is mutated in Werner syndrome4,5.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [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 in the free run.
- cites [5] Multani, A. S. & Chang, S. WRN at telomeres: implications for aging and cancer. J. Cell Sci. 120, 713–721 (2007) source
Not checked in the free run.
- May combine two claims. 18
May combine two claims.
Findingown data§ AbstractPremature cellular senescence was also observed with two independent SIRT6 shRNAs, but not with irrelevant shRNAs.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ AbstractSIRT6 occupancy at telomeric chromatin was observed for both recombinant Flag-tagged SIRT6 and endogenous SIRT6, in both U2OS osteosarcoma cells and primary IMR90 cells.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ AbstractSIRT6 deacetylation activity is highly specific for H3K9Ac, with no deacetylation detected for 12 other acetylated histone peptides.
“This activity was highly specific for H3K9Ac, because no deacetylation was detected for 12 other acetylated histone peptides (Fig. 3a and Supplementary Fig. 11).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ AbstractSIRT6 deacetylates H3K9Ac in the context of purified full-length histone H3, and mutation of conserved catalytic residue H133Y markedly decreases this activity.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ AbstractSIRT6 knockdown (S6KD) cells have a strikingly shortened replicative lifespan, undergoing premature cellular senescence about ten population doublings before control cells.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ AbstractSIRT6 efficiently and specifically deacetylates H3K9Ac in 293T cells, whereas mutant SIRT6 does not.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ AbstractNon-recurrent chromosomal end-to-end fusions were observed in S6KD cells and were more pronounced at later population doublings, but rarely in control cells.
“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).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ AbstractS6KD metaphases showed elevated levels of missing telomere signals (sister telomere loss) and extra telomere signals (telomere doublets).
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown data§ AbstractS6KD cells undergo accelerated senescence and telomere dysfunction in response to stochastic telomere sequence loss, without increased global telomere erosion.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown data§ AbstractSIRT6 is crucial in maintaining a normal replicative life-span and in preventing the premature senescence of human cells.
“We conclude that SIRT6 is crucial in maintaining a normal replicative life-span and in preventing the premature senescence of human cells.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown data§ AbstractSIRT6 is located at telomeric chromatin in S phase and may regulate replication-associated dynamics in telomere structure.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationreasoning§ AbstractSIRT6 collaborates with WRN at telomeric chromatin to ensure efficient telomere replication and to prevent the accrual of structural abnormalities at telomeres.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown data§ AbstractThe regulation of chromatin is linked to telomere function, cellular senescence and potentially organismal ageing.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown data§ AbstractSIRT6 is an NAD-dependent deacetylase with specificity for H3K9Ac.
“Together, these observations indicate that SIRT6 is an NAD-dependent deacetylase with specificity for H3K9Ac.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationreasoning§ AbstractDeacetylation 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.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown data§ AbstractTelomere dysfunction, not BER defects or oxidative stress, underlies the premature senescence phenotype of S6KD cells.
“Together, these findings demonstrate that telomere dysfunction, not BER defects or oxidative stress, underlie the premature senescence phenotype of S6KD cells.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown data§ AbstractSIRT6 contributes to the propagation of a specialized chromatin state at mammalian telomeres, which in turn is required for proper telomere metabolism and function.
“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.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown data§ AbstractThe findings link chromatin regulation by SIRT6 to telomere maintenance and a human premature ageing syndrome.
“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.”
Quote in the paperSubstantial claim
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?
SIRT6 promotes DNA double strand break repair, regulates telomere stability, suppresses inflammation and opposes tumorigenesis.
“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 human cells, loss of SIRT6 causes telomere dysfunction and premature cellular senescence.
“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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Jiao, F., & Gong, Z. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/6782872 · Cited by 293 · see citing works
Mesenchymal Stem/Stromal Cell Senescence: Hallmarks, Mechanisms, and Combating Strategies
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Sirtuins and Type 2 Diabetes: Role in Inflammation, Oxidative Stress, and Mitochondrial Function
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DNA damage response and metabolic disease
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Sirtuins: guardians of mammalian healthspan
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Sirtuins in Epigenetic Regulation
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SIRT6: Novel Mechanisms and Links to Aging and Disease
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The sirtuin SIRT6 deacetylates H3 K56Ac in vivo to promote genomic stability
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- 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
- Health Sciences › Medicine › Physiology › 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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