SIRT6 Links Histone H3 Lysine 9 Deacetylation to NF-κB-Dependent Gene Expression and Organismal Life Span
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Members of the sirtuin (SIRT) family of NAD-dependent deacetylases promote longevity in multiple organisms. Deficiency of mammalian SIRT6 leads to shortened life span and an aging-like phenotype in mice, but the underlying molecular mechanisms are unclear. Here we show that SIRT6 functions at chromatin to attenuate NF-kappaB signaling. SIRT6 interacts with the NF-kappaB RELA subunit and deacetylates histone H3 lysine 9 (H3K9) at NF-kappaB target gene promoters. In SIRT6-deficient cells, hyperacetylation of H3K9 at these target promoters is associated with increased RELA promoter occupancy and enhanced NF-kappaB-dependent modulation of gene expression, apoptosis, and cellular senescence. Computational genomics analyses revealed increased activity of NF-kappaB-driven gene expression programs in multiple Sirt6-deficient tissues in vivo. Moreover, haploinsufficiency of RelA rescues the early lethality and degenerative syndrome of Sirt6-deficient mice. We propose that SIRT6 attenuates NF-kappaB signaling via H3K9 deacetylation at chromatin, and hyperactive NF-kappaB signaling may contribute to premature and normal aging.
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SIRT6 attenuates NF-κB signaling via H3K9 deacetylation at chromatin of NF-κB target gene promoters, which are related to apoptosis and cellular senescence.
“SIRT6 attenuates NF-κB signaling via histone H3 lysine 9 (H3K9) deacetylation at chromatin of NF-κB target gene promoters, which are related to apoptosis, and cellular senescence [108].”
From NAD+ Precursors Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR): Potential Dietary Contribution to Health (2023) · cites this paper as [108]
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 [22]
SIRT6 has multiple biochemical activities, including protein deacetylation and mono-ADP ribosylation.
“SIRT6 has multiple biochemical activities, including protein deacetylation22 and mono-ADP ribosylation19,29.”
From SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age (2014) · cites this paper as [22]
The citation to this paper is attached to mono-ADP ribosylation, not to protein deacetylation. The Introduction and Discussion describe SIRT6 as an H3K9 deacetylase, but searches for mono-ADP ribosylation, ADP-ribosylation, and ADP-ribosyltransferase found no passage addressing that activity. Page numbers were not available in our copy. (LLM, conf=0.72)
Experimental — accuracy not yet measuredNF-κB is regulated by cytokines, growth factors, SIRT1, SIRT6, and FOXO.
“NF-κB is regulated by many upstream factors and regulators including cytokines, growth factors, the deacetylases SIRT1 and SIRT6, and the transcription factor FOXO (Kawahara et al., 2009; Salminen et al., 2008).”
From The Aging Epigenome (2016) · cites this paper as Kawahara et al., 2009
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Zheng, M., Schultz, M. B., & Sinclair, D. A. (2022) · Trends in Immunology · doi:10.1016/j.it.2022.02.001 · Cited by 62 · see citing works
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- Authors
- Kawahara, T. L. A., Michishita, E., Adler, A. S., Damian, M., Berber, E., Lin, M., McCord, R. A., Ongaigui, K. C. L., Boxer, L. D., Chang, H. Y., & Chua, K. F.
- Affiliations
- Stanford Medicine (US)
- VA Palo Alto Health Care System (US)
- Corresponding author
- Chang, Howard Y.
- Chua, Katrin F.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2009-01
- Volume
- 136
- Issue
- 1
- Pages
- 62-74
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2757125
- OpenAlex
- W2063084036
- Cited by
- 1,090
- References
- 38
- Citations by year
- 2026: 35 · 2025: 50 · 2024: 55 · 2023: 63 · 2022: 75 · 2021: 85 · 2020: 69 · 2019: 58 · 2018: 71 · 2017: 63 · 2016: 67 · 2015: 61 · 2014: 59 · 2013: 75 · 2012: 70
- FWCI
- 48.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1658 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG028867, K08AG028961)
- National Cancer Institute (R01CA118750)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- SIRT6, NF-κB signaling, RelA, aging, lifespan, sirtuins, chromatin, gene expression regulation, apoptosis, cellular senescence, haploinsufficiency, NAD+-dependent deacetylase
- MeSH terms
- Acetylation, Animals, Cell Line, Chromatin, Crosses, Genetic, Embryo, Mammalian, Humans, Longevity, Promoter Regions, Genetic, NF-kappa B, Gene Expression Regulation, Developmental, Sirtuins, Mice, Transcription Factor RelA
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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