Affinage

SIRT6

NAD-dependent protein deacylase sirtuin-6 · UniProt Q8N6T7

Length
355 aa
Mass
39.1 kDa
Annotated
2026-06-10
100 papers in source corpus 40 papers cited in narrative 42 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SIRT6 is a nuclear, chromatin-associated NAD+-dependent enzyme that couples DNA-damage sensing, chromatin-based transcriptional repression, and metabolic control (PMID:20729089, PMID:31995034, PMID:31851938). A cryo-EM structure of SIRT6 on the nucleosome shows its zinc finger anchoring to the histone acidic patch while the Rossmann-fold domain detaches DNA from the octamer, positioning the active site over H3 tails to support its substrate-specific deacetylation of H3K9 and H3K56 (PMID:38415718, PMID:20729089). In the DNA-damage response, SIRT6 acts as a direct double-strand-break sensor that recognizes break DNA through a tunnel-like structure and relocates to lesions independently of upstream sensors, triggering ATM recruitment and H2AX phosphorylation (PMID:31995034); it mono-ADP-ribosylates PARP1 at K521 to stimulate poly-ADP-ribosylase activity and enhance repair, and recruits the remodeler CHD4 to relax compacted chromatin for homologous recombination (PMID:21680843, PMID:31970415), with chromatin loading promoted by lamin A (PMID:26549451). Beyond histones, SIRT6 deacetylates and deacylates a broad set of non-histone substrates: it removes long-chain fatty-acyl groups from R-Ras2 to control its membrane localization and PI3K/Akt signaling (PMID:28406396), deacetylates transcription factors and coactivators including NCOA2-K780 to activate PPARalpha-driven beta-oxidation while suppressing lipogenic LXRalpha/ChREBP/SREBP1c programs (PMID:31851938, PMID:34425214), and deacetylates substrates such as TRF2, STAT5, NFATc4, and RORgammat to regulate telomere protein turnover, cytokine signaling, cardiomyocyte hypertrophy, and IL-17A transcription (PMID:27923994, PMID:36496445, PMID:30670969, PMID:38135684). As a chromatin repressor it docks at promoters and deacetylates H3K9/H3K56 to silence inflammatory and developmental genes including TNFSF4, IL-1beta, and Notch1/4 (PMID:27249230, PMID:37394473, PMID:28871079), and it restrains transcriptional elongation by binding RNA Pol II and stabilizing promoter-proximal NELF pausing (PMID:31399344). SIRT6 also represses LINE1 retrotransposition, preventing cytoplasmic L1 cDNA from activating cGAS-driven interferon responses (PMID:30853213). These activities integrate into organism-level roles in hepatic lipid and glucose metabolism, adipose thermogenesis, and lifespan extension (PMID:30530497, PMID:34050173, PMID:28723567).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2010 Medium

    Establishing SIRT6 as a substrate-specific histone deacetylase defined the core enzymatic activity through which it acts on chromatin in telomere maintenance, gene expression, and repair.

    Evidence In vitro deacetylase assays with histone substrates, ChIP, and genetic deletion models consolidated in review

    PMID:20729089

    Open questions at the time
    • Does not resolve how target specificity at individual promoters is achieved
    • Non-histone substrates not yet defined
  2. 2011 High

    Discovery that SIRT6 mono-ADP-ribosylates PARP1 at K521 showed it stimulates DSB repair through a second, non-deacetylase enzymatic activity beyond histone deacetylation.

    Evidence Co-IP, in vitro mono-ADP-ribosylation assay, K521 mutagenesis, and DSB repair assays under oxidative stress

    PMID:21680843

    Open questions at the time
    • How SIRT6 is recruited to breaks not addressed here
    • Relative contribution of ribosylation vs deacetylation to repair unquantified
  3. 2015 High

    Identification of lamin A as an endogenous activator linked nuclear architecture to SIRT6 chromatin loading and DDR function, and connected progerin to impaired repair.

    Evidence Reciprocal Co-IP, chromatin fractionation, SIRT6 enzymatic assays with lamin A/progerin manipulation and DDR readouts

    PMID:26549451

    Open questions at the time
    • Structural basis of lamin A activation unknown
    • Whether activation is direct or via cofactor recruitment unclear
  4. 2015 Medium

    SIRT6 interactions with the BER enzymes MYH/APE1 and the 9-1-1 clamp connected it to oxidative DNA damage processing in active chromatin.

    Evidence Co-IP, pulldown assays, MYH interdomain mutagenesis, and live-cell imaging at oxidative damage sites

    PMID:26063178

    Open questions at the time
    • Enzymatic consequence of these interactions for BER not established
    • Single-lab interaction data
  5. 2017 High

    Demonstration that SIRT6 defatty-acylates R-Ras2 established a deacylase activity controlling GTPase membrane localization and PI3K/Akt signaling, extending SIRT6 substrates beyond histones.

    Evidence SIRT6 KO MEFs, in vitro defatty-acylation assay, fractionation, R-Ras2/PI3K Co-IP, and Akt/proliferation readouts

    PMID:28406396

    Open questions at the time
    • Scope of acylated substrate repertoire unknown
    • In vivo relevance in tumor settings not tested here
  6. 2017 High

    SIRT6 deacetylation of the TRF2 TRFH domain triggering its ubiquitin-dependent degradation linked SIRT6 to telomere protein turnover under replication stress.

    Evidence Reciprocal Co-IP, in vivo deacetylation, ubiquitylation assays, and TRF2 domain-mapping mutants

    PMID:27923994

    Open questions at the time
    • Ubiquitin ligase responsible not identified
    • Telomere phenotype consequences not fully mapped
  7. 2017 Medium

    Multiple studies extended SIRT6 to non-histone substrate deacetylation in signaling — STAT5-K163 in chondrocytes and PGC-1alpha activation via ATF2 in adipose thermogenesis.

    Evidence Co-IP, MS site identification, K163R mutagenesis, ChIP, and tissue-specific KO mice

    PMID:28723567 PMID:36496445

    Open questions at the time
    • Whether ATF2 is a direct deacetylation substrate not resolved
    • Tissue specificity of these axes not generalized
  8. 2018 High

    CRISPR SIRT6 knockout in non-human primate revealed an essential role in neurodevelopment via H3 deacetylation at the H19 imprinting control region, controlling CTCF recruitment and neuronal differentiation timing.

    Evidence CRISPR-Cas9 KO in cynomolgus monkey, ChIP for histone acetylation and CTCF, and human neural progenitor validation

    PMID:30135584

    Open questions at the time
    • Direct demonstration that SIRT6 binds the H19 ICR not shown
    • Generalizability to other imprinted loci unknown
  9. 2018 Medium

    Phosphorylation of SIRT6 at T294 by PKCzeta defined a post-translational mechanism stimulating SIRT6 chromatin enrichment and beta-oxidation gene activation.

    Evidence In vitro kinase assay, T294 mutagenesis, Co-IP, and ChIP at beta-oxidation promoters

    PMID:30504065

    Open questions at the time
    • Effect of T294 phosphorylation on enzymatic activity per se not measured
    • Single cancer cell context
  10. 2019 High

    SIRT6 was defined as a metabolic transcriptional coordinator — activating PPARalpha/beta-oxidation through NCOA2-K780 deacetylation while suppressing SREBP-dependent lipid synthesis — and as a repressor of LINE1-driven cGAS interferon responses.

    Evidence ChIP, Co-IP, in vitro NCOA2 deacetylation, mouse metabolomics with 13C tracing; KO mice with NRTI rescue and L1 cDNA/interferon readouts

    PMID:30853213 PMID:31851938

    Open questions at the time
    • How SIRT6 silences L1 loci mechanistically not fully defined
    • Direct vs indirect control of SREBP activity not separated
  11. 2019 High

    Discovery that SIRT6 stabilizes NELF-mediated Pol II pausing established a role in restraining transcriptional elongation, mechanistically linking H3K9ac/H3K56ac removal to elongation control.

    Evidence Co-IP of SIRT6 with Pol II and NELF, ChIP-seq for histone marks and elongation factors, CDK9 activity assays

    PMID:31399344

    Open questions at the time
    • Whether NELF stabilization is deacetylation-dependent not fully isolated
    • Genome-wide scope of paused genes regulated unclear
  12. 2020 High

    SIRT6 was shown to be an intrinsic DSB sensor that directly binds break DNA via a tunnel-like structure and triggers ATM recruitment, explaining how it arrives at lesions independently of canonical sensors.

    Evidence In vitro DNA-binding assays comparing DSB vs intact DNA, live-cell laser-damage imaging, epistasis with DDR sensors

    PMID:31995034

    Open questions at the time
    • Structural basis of the DNA-binding tunnel not solved
    • Relationship to lamin A-dependent recruitment unresolved
  13. 2020 High

    SIRT6 recruitment of CHD4 to displace HP1 from H3K9me3 defined how it enables HR within compacted, heterochromatic regions in an ATM-dependent manner.

    Evidence Reciprocal Co-IP, ChIP, live-cell CHD4 imaging, HR assays, and ATM-inhibition epistasis

    PMID:31970415

    Open questions at the time
    • Order of SIRT6/CHD4/ATM events not fully resolved
    • Direct CHD4 interaction interface not mapped
  14. 2021 Medium

    A series of substrate-deacetylation studies expanded SIRT6's metabolic and homeostatic substrate map to LXRalpha/ChREBP/SREBP1c, ERRgamma, FXR, and Crebh, defining hepatic lipid, ketogenic, and protective programs, alongside gluconeogenesis-driven lifespan extension.

    Evidence Co-IP and in vivo deacetylation assays with hepatocyte-specific KO, rescue, and epistasis; transgenic mice with 13C lactate tracing and multi-omics

    PMID:30530497 PMID:32701506 PMID:34050173 PMID:34425214 PMID:35526796

    Open questions at the time
    • Direct deacetylation sites not defined for all factors
    • Upstream signal integrating these axes biochemically unclear
  15. 2021 Medium

    SIRT6 was placed in mitochondrial and antioxidant regulation through YY1-dependent control of mitochondrial gene expression and stabilization of NRF2 against Keap1.

    Evidence Brain-specific KO transcriptomics/metabolomics with SIRT6-YY1 Co-IP and SIRT3/SIRT4 rescue; Co-IP/GST pulldown with NRF2 stability assays

    PMID:36356655 PMID:36653345

    Open questions at the time
    • Whether YY1 or NRF2 are direct enzymatic substrates not established
    • Single-lab interaction evidence
  16. 2024 High

    The cryo-EM structure of SIRT6 on the nucleosome resolved how it engages chromatin — zinc finger anchoring to the acidic patch and DNA unwrapping positioning the NAD+ pocket over H3 tails — providing the structural basis for its histone deacetylase specificity.

    Evidence Cryo-EM structure determination with molecular dynamics simulation of histone tail positioning

    PMID:38415718

    Open questions at the time
    • Structure of SIRT6 engaging DSB DNA or non-histone substrates not solved
    • How activators like lamin A or NAEs alter this engagement unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How SIRT6's three distinct enzymatic activities (deacetylation, defatty-acylation, mono-ADP-ribosylation) are selectively deployed at specific substrates and loci, and how upstream signals and activators switch between them, remains unresolved.
  • No unified model for activity selection among substrates
  • Structural basis for deacylase vs deacetylase mode not defined
  • In vivo demyristoylation of pro-TNFalpha not directly demonstrated enzymatically

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0140110 transcription regulator activity 3 GO:0016740 transferase activity 2 GO:0042393 histone binding 2 GO:0003677 DNA binding 1
Localization
GO:0000228 nuclear chromosome 3 GO:0005634 nucleus 3 GO:0005730 nucleolus 1
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-168256 Immune System 4 R-HSA-73894 DNA Repair 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-4839726 Chromatin organization 3
Partners
CHD4NCOA2NELFPARP1RNA POL IIRORGAMMATSTAT5TRF2

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 SIRT6 physically associates with PARP1 and mono-ADP-ribosylates PARP1 on lysine residue 521, thereby stimulating PARP1 poly-ADP-ribosylase activity and enhancing DNA double-strand break repair under oxidative stress. SIRT6 is recruited to sites of DSBs and stimulates repair through both NHEJ and HR. Co-immunoprecipitation, in vitro mono-ADP-ribosylation assay, site-directed mutagenesis (K521), DSB repair assays in mammalian cells under oxidative stress Science High 21680843
2019 SIRT6-deficient cells accumulate cytoplasmic LINE1 (L1) cDNA, which triggers a type I interferon response via activation of cGAS, contributing to sterile inflammation. SIRT6 normally represses L1 retrotransposition, and inhibiting L1 with NRTIs or siRNA abrogates the interferon response and DNA damage markers in SIRT6 KO cells. SIRT6 knockout mouse model, siRNA knockdown, NRTI treatment, cytoplasmic L1 cDNA quantification, interferon response measurement, cGAS pathway analysis Cell Metabolism High 30853213
2015 Lamin A is an endogenous activator of SIRT6 that facilitates chromatin localization of SIRT6 upon DNA damage. Lamin A promotes SIRT6-dependent DNA-PKcs recruitment to chromatin, CtIP deacetylation, and PARP1 mono-ADP-ribosylation in response to DNA damage. Progerin (mutant lamin A) jeopardizes SIRT6 activation and compromises these DNA repair events. Co-immunoprecipitation, chromatin fractionation, SIRT6 enzymatic assays, lamin A/progerin overexpression and knockdown, DNA damage response readouts (DNA-PKcs recruitment, CtIP deacetylation) Cell Reports High 26549451
2020 SIRT6 directly recognizes DNA double-strand breaks through a tunnel-like structure with high affinity for DSB DNA, and relocates to damage sites independently of known signaling or sensors. SIRT6 acts as a DSB sensor by triggering ATM recruitment, H2AX phosphorylation, and recruitment of HR and NHEJ pathway proteins. In vitro DNA binding assays (DSB vs. intact DNA), live-cell imaging of SIRT6 recruitment to laser-induced damage, epistasis with known DDR sensors, ATM recruitment and γH2AX assays eLife High 31995034
2020 SIRT6 coordinates with the chromatin remodeler CHD4 to promote chromatin relaxation at DNA damage sites. Upon DNA damage, SIRT6 translocates to damage sites, interacts with and recruits CHD4, which then displaces HP1 from H3K9me3, enabling HR in compacted chromatin in a manner dependent on ATM. Co-immunoprecipitation, chromatin immunoprecipitation, live-cell imaging of CHD4 recruitment, HR assays, SIRT6/CHD4 knockdown with DNA repair readouts, ATM inhibition epistasis Nucleic Acids Research High 31970415
2017 SIRT6 regulates R-Ras2 (a Ras family GTPase) through lysine defatty-acylation. In SIRT6 KO mouse embryonic fibroblasts, R-Ras2 lysine fatty acylation is increased, promoting plasma membrane localization of R-Ras2 and its interaction with PI3K, leading to activated Akt and increased cell proliferation. SIRT6 knockout MEFs, in vitro defatty-acylation assay, subcellular fractionation, co-immunoprecipitation (R-Ras2/PI3K), Akt phosphorylation readout, cell proliferation assay eLife High 28406396
2019 SIRT6 binds PPARα and its response elements within promoter regions to activate β-oxidation gene transcription. SIRT6 also binds PPARα coactivator NCOA2 and decreases hepatic NCOA2 K780 acetylation, stimulating its activation of PPARα in a SIRT6-dependent manner. SIRT6 further mediates PPARα inhibition of SREBP-dependent cholesterol and triglyceride synthesis. ChIP, Co-immunoprecipitation, SIRT6 heterozygous and transgenic mouse metabolomics, in vitro deacetylation of NCOA2, gene expression analyses, 13C metabolic tracing Cell Reports High 31851938
2024 Cryo-EM structure of human SIRT6 bound to a nucleosome reveals that the zinc finger domain of SIRT6 associates with the acidic patch of the nucleosome through multiple arginine anchors, while the Rossmann fold domain binds the terminus of the looser DNA half, detaching two turns of DNA from the histone octamer and placing the NAD+ binding pocket close to the DNA exit site, poising the active site to deacetylate H3 histone tails including lysines close to the H3 core. Cryo-EM structure determination, molecular dynamics simulations of histone tails in nucleosome-bound SIRT6 complex eLife High 38415718
2017 SIRT6 interacts with phospho-ATF2 and promotes its binding to the PGC-1α gene promoter to activate PGC-1α expression, thereby regulating thermogenic gene expression in brown and beige adipose tissue. Cold exposure and β-adrenergic stimulation induce SIRT6 in fat; adipose-specific SIRT6 deletion impairs brown fat thermogenesis. Co-immunoprecipitation (SIRT6-ATF2), ChIP (ATF2 on PGC-1α promoter), adipose-specific SIRT6 KO mice, thermogenic gene expression assays, oxygen consumption measurement Cell Reports Medium 28723567
2010 SIRT6 functions as a highly substrate-specific histone deacetylase that targets H3K9 and H3K56 acetylation to regulate chromatin in the context of telomere maintenance, genome stabilization, gene expression, and DNA repair. In vitro deacetylase assays with histone substrates, chromatin immunoprecipitation, genetic deletion models Trends in Biochemical Sciences Medium 20729089
2017 SIRT6 directly interacts with STAT5 and deacetylates STAT5 at conserved lysine 163, thereby inhibiting IL-15/JAK3-induced STAT5 nuclear translocation and inactivating IL-15/JAK3/STAT5 signaling in chondrocytes. Mutation of K163 to arginine in STAT5 abolished SIRT6's regulatory effect. Co-immunoprecipitation, mass spectrometry identification of K163 acetylation site, site-directed mutagenesis (K163R), STAT5 nuclear translocation assays, chondrocyte-specific SIRT6 KO mice, in vivo OA models Nature Communications High 36496445
2017 SIRT6 directly interacts with TRF2 in a DNA-independent manner; this interaction increases upon replication stress. SIRT6 deacetylates the TRFH domain of TRF2 in vivo, which leads to TRF2 ubiquitylation and ubiquitin-dependent proteolysis. SIRT6 knockdown stabilizes TRF2 protein and counteracts its downregulation during DNA damage response. Co-immunoprecipitation, in vivo deacetylation assays, ubiquitylation assays, TRF2 mutant (TRF2cT) overexpression, SIRT6 knockdown with TRF2 protein stability readout Nucleic Acids Research High 27923994
2016 SIRT6 regulates Tau protein stability and phosphorylation through increased activation of the kinase GSK3α/β. Brain-specific SIRT6-deficient mice accumulate hyperphosphorylated Tau (a neurotoxic form), with increased DNA damage and cell death. SIRT6 deacetylates Tau at K174, and its loss leads to nuclear Tau-K174ac accumulation. Brain-specific SIRT6 KO mice, Western blotting for phospho-Tau and GSK3 activation, behavioral assays, loss-of-function with defined molecular phenotype Cell Reports Medium 28355558
2021 SIRT6 deacetylates Tau at lysine 174 in the nucleus. Nuclear Tau-K174ac accumulation (caused by loss of SIRT6 or chronic DNA damage) induces global gene expression changes affecting protein translation, synthesis, and energy production. Alzheimer's disease patient brains show increased nuclear Tau-K174ac coincident with decreased SIRT6. SIRT6 KO cells and neurons, acetylation-mimetic Tau mutants, nuclear fractionation, transcriptomic analysis, immunofluorescence in human AD brain tissue Cell Reports Medium 33910019
2019 SIRT6 restrains transcriptional elongation by binding to RNA Pol II and preventing release of the negative elongation factor (NELF), thereby stabilizing Pol II promoter-proximal pausing. SIRT6 genetic depletion or chromatin deficiency upon glucose deprivation causes intragenic enrichment of H3K9ac and H3K56ac, CDK9 activation (which phosphorylates NELF and Pol II CTD), and enrichment of positive elongation factors, leading to increased gene expression. Co-immunoprecipitation (SIRT6-Pol II, SIRT6-NELF), ChIP-seq for H3K9ac/H3K56ac and elongation factors, CDK9 activity assays, SIRT6 KO transcriptomic analysis Molecular Cell High 31399344
2015 SIRT6 interacts with and stimulates MYH glycosylase and APE1 endonuclease (base excision repair enzymes), and also interacts with the Rad9-Rad1-Hus1 (9-1-1) checkpoint clamp. These interactions are enhanced after oxidative stress. APE1 and Hus1 act together to stabilize the MYH/SIRT6 complex. SIRT6 and MYH co-localize at sites of oxidative DNA damage in transcriptionally active chromatin. Co-immunoprecipitation, pulldown assays, mutagenesis of MYH interdomain connector, live-cell imaging at confined oxidative damage sites, telomere co-localization assays BMC Molecular Biology Medium 26063178
2018 PKCζ physically interacts with SIRT6 and phosphorylates SIRT6 at threonine 294, promoting SIRT6 enrichment on chromatin and stimulating expression of fatty acid β-oxidation genes (ACSL1, CPT1, CACT, HADHB) at their promoters in colon cancer cells after palmitic acid treatment. Co-immunoprecipitation (PKCζ-SIRT6 in vitro and in vivo), site-directed mutagenesis (T294), ChIP on β-oxidation gene promoters, PKCζ kinase assay Neoplasia Medium 30504065
2021 SIRT6 controls hepatic lipogenesis by directly interacting with and deacetylating LXRα, ChREBP, and SREBP1c transcription factors, suppressing their transcriptional activities. Hepatic SIRT6 deficiency elevates ChREBP and SREBP1c levels and activity, promoting fatty liver disease. Co-immunoprecipitation (SIRT6-LXRα, SIRT6-ChREBP, SIRT6-SREBP1c), in vitro and in vivo deacetylation assays, liver-specific SIRT6 KO mice on Western diet Biochimica et Biophysica Acta – Molecular Basis of Disease Medium 34425214
2020 SIRT6 deacetylates ERRγ, destabilizing ERRγ protein and inhibiting its transcriptional activity, thereby protecting against cholestatic liver injury. Hepatocyte-specific SIRT6 KO worsens cholestasis; adenoviral SIRT6 re-expression reverses damage. In human cholestasis patients, SIRT6 is decreased and acetylated ERRγ is increased. Hepatocyte-specific SIRT6 KO mice (bile duct ligation model), adenoviral SIRT6 rescue, in vivo deacetylation of ERRγ, ERRγ protein stability assay, ERRγ KD epistasis, human patient tissue analysis JCI Insight Medium 32701506
2022 SIRT6 deacetylates FXR (farnesoid X receptor), elevating FXR transcriptional activity and protecting against APAP-induced hepatotoxicity via improved glutathione metabolism. FXR ablation blunts SIRT6 overexpression-mediated protective effects. Hepatocyte-specific SIRT6 KO mice, in vivo FXR deacetylation assay, FXR KO epistasis, pharmacological SIRT6 activation, RNA-seq Cellular and Molecular Gastroenterology and Hepatology Medium 35526796
2021 SIRT6 inhibits Notch1 and Notch4 transcription in podocytes by deacetylating histone H3K9 at their promoters. Podocyte-specific Sirt6 deletion exacerbates podocyte injury and proteinuria through upregulation of Notch signaling. Podocyte-specific SIRT6 KO mice in diabetic and adriamycin nephropathy models, ChIP (H3K9ac at Notch promoters), gene expression analysis Nature Communications Medium 28871079
2018 SIRT6 loss in non-human primate (cynomolgus monkey) causes histone hyperacetylation at the imprinting control region of H19, leading to CTCF recruitment and upregulation of the long non-coding RNA H19 (a developmental repressor), thereby delaying neuronal differentiation. This was recapitulated in human neural progenitor cell differentiation. CRISPR-Cas9 SIRT6 KO in cynomolgus monkeys, ChIP for histone acetylation at H19 ICR, CTCF ChIP, H19 expression analysis, human neural progenitor differentiation model Nature High 30135584
2015 SIRT6 interacts with Runx2 and osterix transcription factors and deacetylates histone H3K9 at their promoters. SIRT6 also deacetylates H3K9 at the promoters of Dkk1 and osteoprotegerin. Excessive SIRT6 deficiency results in elevated Runx2/Osx causing impaired osteoblastogenesis, and up-regulated Dkk1/osteoprotegerin contributing to low-turnover osteopenia. Co-immunoprecipitation (SIRT6-Runx2, SIRT6-Osx), ChIP for H3K9ac at Dkk1/osteoprotegerin/Runx2/Osx promoters, SIRT6 KO bone phenotype analysis Bone Medium 26189760
2017 SIRT6 represses myostatin (Mstn) expression in muscle cells by attenuating NF-κB binding to the Mstn promoter, as demonstrated by ChIP. SIRT6 KO mice show elevated myostatin and degenerated skeletal muscle phenotype with fibrosis. ChIP (NF-κB at Mstn promoter), SIRT6 KO mice, overexpression in C2C12 cells, cancer cachexia in vivo model Scientific Reports Medium 28928419
2018 SIRT6 represses Fsp27β expression by interacting with Crebh and preventing its recruitment to the Fsp27β gene promoter. This Sirt6-Crebh-Fsp27 axis is pivotal for hepatic ketogenesis and lipid metabolism; HKO mice on ketogenic diet show impaired ketogenesis rescued by Fsp27 silencing. Co-immunoprecipitation (SIRT6-Crebh), ChIP (Crebh at Fsp27β promoter), hepatocyte-specific SIRT6 KO mice, Fsp27 siRNA rescue experiment Journal of Biological Chemistry Medium 30530497
2022 In macrophages, a subpopulation of normally unstable SIRT6 is rapidly stabilized upon LPS stimulation and localizes to the cytoplasm near the endoplasmic reticulum, where it promotes TNFα secretion (likely through demyristoylation of pro-TNFα). SIRT6 inhibition dampens TNFα secretion in vitro and in vivo (septic shock model). Western blot and immunofluorescence in Raw264.7, bone marrow, and peritoneal macrophages with LPS stimulation; SIRT6 inhibitor in vivo (LPS-induced septic shock); SIRT6 KD in obese mice Journal of Biological Chemistry Medium 35150745
2016 SIRT6 decreases TNFSF4 gene expression in endothelial cells by binding to and deacetylating H3K9 at the TNFSF4 gene promoter, reducing monocyte adhesion and protecting against atherosclerosis. ChIP (SIRT6 and H3K9ac at TNFSF4 promoter), SIRT6 KO endothelial cells and ApoE-/- mice, RNA-seq, monocyte adhesion assays Aging Medium 27249230
2021 SIRT6 is a central regulator of mitochondrial gene expression in the brain through its interaction with transcription factor YY1, together regulating mitochondrial gene expression. SIRT6 target genes include SIRT3 and SIRT4; loss of SIRT6 leads to decreased mitochondrial gene expression, increased ROS, reduced mitochondrial number, and impaired membrane potential, partially rescued by restoring SIRT3 and SIRT4. Brain-specific SIRT6 KO transcriptomics and metabolomics, Co-immunoprecipitation (SIRT6-YY1), SIRT3/SIRT4 restoration rescue experiments, mitochondrial functional assays (ROS, membrane potential, mitochondrial number) Cell Death & Disease Medium 36653345
2022 SIRT6 suppresses NFATc4 expression and activation in cardiomyocytes through deacetylase activity; interactions between SIRT6 and NFATc4 facilitate NFATc4 deacetylation, preventing NFATc4 nuclear translocation and transcriptional activation of hypertrophic genes. Deacetylase-inactive SIRT6-H133Y mutant fails to suppress NFATc4. Co-immunoprecipitation (SIRT6-NFATc4), adenoviral overexpression of SIRT6 and SIRT6-H133Y, NFATc4 nuclear translocation assays, NFATc4 phosphorylation and acetylation assays, BNP expression readouts Frontiers in Pharmacology Medium 30670969
2020 SIRT6 interacts with PARP1 and activates PARP1 polyADP-ribosylase activity in leukemia cells, leading to ADP-ribosylation of HMGB1 which influences HMGB1 acetylation and promotes HMGB1 cytoplasmic translocation during chemotherapy-induced autophagy. Co-immunoprecipitation (SIRT6-PARP1), SIRT6/PARP1 knockdown, HMGB1 ADP-ribosylation and acetylation assays, HMGB1 translocation assays in leukemia cells Cancer Biology & Therapy Medium 31928132
2023 SIRT6 directly interacts with RORγt and deacetylates RORγt at lysine 192 (via SIRT6's PPXY motifs), promoting RORγt recruitment to the IL-17A gene promoter and enhancing IL-17A transcription. Airway epithelial cell-specific SIRT6 deletion protects against allergen-induced IL-17A-dependent airway inflammation. Co-immunoprecipitation (SIRT6-RORγt), in vivo deacetylation at K192, luciferase reporter assays for IL-17A promoter, airway epithelial-specific SIRT6 KO mice in allergen challenge model Nature Communications Medium 38135684
2023 SIRT6 epigenetically represses IL-1β transcription in vascular smooth muscle cells by binding to the Il1b promoter and reducing H3K9 and H3K56 acetylation, as shown by ChIP. VSMC-specific SIRT6 KO accelerates thoracic aortic aneurysm formation, rescued by IL-1β genetic KO or pharmacological IL-1β antagonism. ChIP (SIRT6 and H3K9ac/H3K56ac at Il1b promoter), VSMC-specific SIRT6 KO mice (angiotensin II model), Il1b KO epistasis, anakinra pharmacological rescue Signal Transduction and Targeted Therapy Medium 37394473
2022 SIRT6 overexpression suppresses PPARγ expression in endothelial cells through SIRT6-dependent deacetylation of histone H3K9 around the PPARγ promoter, resulting in reduced PPARγ-driven endothelial fatty acid uptake. Restoring endothelial SIRT6 in diabetic mice decreases cardiac lipid accumulation and diastolic dysfunction. ChIP (H3K9ac at PPARγ promoter), SIRT6 conditional transgenic and KO endothelial mouse models, PPARγ gain-of-function epistasis, endothelial FA uptake assays Circulation Research Medium 36278398
2021 SIRT6 overexpression extends lifespan and reduces frailty in mice through improvement of gluconeogenesis: SIRT6 increases hepatic gluconeogenic gene expression, enhances de novo NAD+ synthesis, and systemically increases glycerol release from adipose tissue. 13C lactate tracing confirmed improved utilization of gluconeogenic precursors in aged SIRT6-transgenic mice. SIRT6-transgenic mice (both sexes), 13C lactate tracing, in vivo multi-omics (transcriptomics/metabolomics), gluconeogenic gene expression analysis, NAD+ measurement Nature Communications Medium 34050173
2017 SIRT6 inhibits Notch1/Notch4 transcription in podocytes by deacetylating H3K9 at their promoters, and reduces urokinase plasminogen activator receptor (uPAR) expression, which is a key factor for podocyte foot process effacement and proteinuria. ChIP for H3K9ac at Notch promoters, podocyte-specific SIRT6 KO in diabetic nephropathy and adriamycin nephropathy mouse models Nature Communications Medium 28871079
2022 SIRT6 mediates antioxidative functions by physically interacting with NRF2 (confirmed by Co-IP and GST pulldown) and decreasing NRF2 binding to its inhibitor Keap1, thereby enhancing NRF2 protein stability and nuclear accumulation. SIRT6-deficient MEFs show faster NRF2 degradation; SIRT6 overexpression increases Nrf2 protein content. Co-immunoprecipitation, GST pulldown (SIRT6-NRF2 interaction), NRF2 protein stability assays in Sirt6+/- MEFs vs. WT, overexpression studies, Keap1-NRF2 interaction assay with SIRT6 Experimental Cell Research Medium 36356655
2015 N-acylethanolamines (NAEs) bind to SIRT6 and stimulate its deacetylase activity; oleoylethanolamide has the strongest activating effect (EC50 = 3.1 μM). Quercetin and luteolin show dual functionality, inhibiting SIRT6 at low concentrations and stimulating it at higher concentrations. In vitro SIRT6 deacetylase activity assays with NAEs, quercetin, and luteolin; binding assays; EC50/IC50 determination ChemBioChem Medium 26607666
2022 Drosophila Sirt6 (dSirt6) is a nuclear, chromatin-associated protein with NAD+-dependent histone deacetylase activity. dSirt6 overexpression reduces ribosome biogenesis gene expression (including dMyc target genes) and partially rescues dMyc overexpression effects; dMyc haploinsufficiency does not additively extend lifespan in dSirt6 OE flies, placing dSirt6 upstream of dMyc in lifespan regulation. Drosophila dSirt6 characterization (subcellular localization, in vitro HAD assay), overexpression and knockdown lifespan assays, transcriptomics, genetic epistasis with dMyc (haploinsufficiency and OE rescue) PNAS Medium 35091469
2017 SIRT6 loss in brain promotes GSK3α/β activation, leading to hyperphosphorylation and increased stability of Tau protein. SIRT6 depletion results in increased learning and behavioral deficits, DNA damage, and cell death in brain-specific KO mice. Brain-specific SIRT6 KO mice, Western blotting for phospho-Tau and GSK3 activity, behavioral tests, immunofluorescence for DNA damage markers Cell Reports Medium 28355558
2023 SIRT6 promotes NCOA4-dependent autophagic degradation of ferritin (ferritinophagy), thereby driving sensitivity to ferroptosis in anaplastic thyroid cancer cells. SIRT6 overexpression increases ferroptosis sensitivity; SIRT6 KO promotes ferroptosis resistance. SIRT6 overexpression and KO in thyroid cancer cells, ferroptosis inducers (RSL3, erastin), NCOA4-dependent ferritinophagy assays, flow cytometry (cell death/lipid peroxidation) American Journal of Cancer Research Low 36895980
2022 SIRT6 promotes ERK1/2-driven phosphorylation of DRP1 at serine-616, inducing mitochondrial fission in ovarian cancer cells. This promotes invadopodia formation and cellular invasion. SIRT6 siRNA reduces DRP1 phosphorylation, mitochondrial fragmentation, and invasion. SIRT6 siRNA knockdown and overexpression in ovarian cancer cells, ERK1/2 phosphorylation assays, DRP1 pS616 measurement, mitochondrial morphology analysis, invasion assays FEBS Open Bio Low 35686673
2021 SIRT6 represses FOXO3a binding to the SIRT6 promoter (i.e., FOXO3a promotes SIRT6 transcription) and, downstream, SIRT6 suppresses aerobic glycolysis in melanoma. SIRT6 knockdown or overexpression rescues FOXO3a-driven changes in glycolysis, glucose uptake, and lactate production. ChIP and luciferase assays (FOXO3a at SIRT6 promoter), lentiviral SIRT6 overexpression/knockdown to rescue FOXO3a effects, glucose/lactate assays, Seahorse flux assay, tumor xenograft International Journal of Oncology Low 32124950

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 SIRT6 promotes DNA repair under stress by activating PARP1. Science (New York, N.Y.) 696 21680843
2019 LINE1 Derepression in Aged Wild-Type and SIRT6-Deficient Mice Drives Inflammation. Cell metabolism 389 30853213
2014 Chromatin and beyond: the multitasking roles for SIRT6. Trends in biochemical sciences 299 24438746
2017 Sirt6 deficiency exacerbates podocyte injury and proteinuria through targeting Notch signaling. Nature communications 291 28871079
2016 SIRT6: Novel Mechanisms and Links to Aging and Disease. Trends in endocrinology and metabolism: TEM 215 27836583
2020 SIRT6 Protects Smooth Muscle Cells From Senescence and Reduces Atherosclerosis. Circulation research 203 33353368
2019 SIRT6, a Mammalian Deacylase with Multitasking Abilities. Physiological reviews 191 31437090
2021 Restoration of energy homeostasis by SIRT6 extends healthy lifespan. Nature communications 155 34050173
2020 Emerging roles of SIRT6 in human diseases and its modulators. Medicinal research reviews 152 33325563
2018 SIRT6 deficiency results in developmental retardation in cynomolgus monkeys. Nature 150 30135584
2013 SIRT6 modulates paclitaxel and epirubicin resistance and survival in breast cancer. Carcinogenesis 134 23514751
2022 Melatonin inhibits ferroptosis and delays age-related cataract by regulating SIRT6/p-Nrf2/GPX4 and SIRT6/NCOA4/FTH1 pathways. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 131 36463827
2022 SIRT6 in Aging, Metabolism, Inflammation and Cardiovascular Diseases. Aging and disease 131 36465178
2010 Chromatin regulation and genome maintenance by mammalian SIRT6. Trends in biochemical sciences 126 20729089
2008 SIRT6 in DNA repair, metabolism and ageing. Journal of internal medicine 123 18226091
2017 Neuroprotective Functions for the Histone Deacetylase SIRT6. Cell reports 122 28355558
2022 Sirt6 attenuates chondrocyte senescence and osteoarthritis progression. Nature communications 112 36496445
2020 SIRT6 is a DNA double-strand break sensor. eLife 112 31995034
2017 Cold-Inducible SIRT6 Regulates Thermogenesis of Brown and Beige Fat. Cell reports 112 28723567
2015 Lamin A Is an Endogenous SIRT6 Activator and Promotes SIRT6-Mediated DNA Repair. Cell reports 106 26549451
2018 The Role of Sirt6 in Obesity and Diabetes. Frontiers in physiology 104 29535637
2016 SIRT6 protects against endothelial dysfunction and atherosclerosis in mice. Aging 104 27249230
2014 SIRT6 promotes COX-2 expression and acts as an oncogene in skin cancer. Cancer research 96 25320180
2023 SIRT1 and SIRT6: The role in aging-related diseases. Biochimica et biophysica acta. Molecular basis of disease 95 37499928
2023 SIRT6-regulated macrophage efferocytosis epigenetically controls inflammation resolution of diabetic periodontitis. Theranostics 92 36593966
2021 Cyclosporine modulates neutrophil functions via the SIRT6-HIF-1α-glycolysis axis to alleviate severe ulcerative colitis. Clinical and translational medicine 87 33634990
2019 SIRT6 Promotes Hepatic Beta-Oxidation via Activation of PPARα. Cell reports 85 31851938
2022 SIRT6 Mitigates Heart Failure With Preserved Ejection Fraction in Diabetes. Circulation research 76 36278398
2020 SIRT6 coordinates with CHD4 to promote chromatin relaxation and DNA repair. Nucleic acids research 75 31970415
2017 SIRT6 regulates Ras-related protein R-Ras2 by lysine defatty-acylation. eLife 75 28406396
2015 The complex role of SIRT6 in carcinogenesis. Carcinogenesis 75 26717993
2013 SIRT6, a protein with many faces. Biogerontology 74 24213807
2016 p53-dependent SIRT6 expression protects Aβ42-induced DNA damage. Scientific reports 70 27156849
2021 Emerging Therapeutic Potential of SIRT6 Modulators. Journal of medicinal chemistry 69 34213345
2023 SIRT6 is a key regulator of mitochondrial function in the brain. Cell death & disease 67 36653345
2021 SIRT6 in Senescence and Aging-Related Cardiovascular Diseases. Frontiers in cell and developmental biology 66 33855020
2021 The Two-Faced Role of SIRT6 in Cancer. Cancers 59 33800266
2011 Repairing split ends: SIRT6, mono-ADP ribosylation and DNA repair. Aging 59 21946623
2019 SIRT6 regulates the proliferation and apoptosis of hepatocellular carcinoma via the ERK1/2 signaling pathway. Molecular medicine reports 54 31257493
2019 The Histone Deacetylase SIRT6 Restrains Transcription Elongation via Promoter-Proximal Pausing. Molecular cell 54 31399344
2013 The histone deacetylase SIRT6: at the crossroads between epigenetics, metabolism and disease. Current topics in medicinal chemistry 52 24171769
2023 Cartilage-specific Sirt6 deficiency represses IGF-1 and enhances osteoarthritis severity in mice. Annals of the rheumatic diseases 49 37550003
2023 Epithelial SIRT6 governs IL-17A pathogenicity and drives allergic airway inflammation and remodeling. Nature communications 47 38135684
2017 SIRT6 interacts with TRF2 and promotes its degradation in response to DNA damage. Nucleic acids research 47 27923994
2022 Sirt6 regulates lifespan in Drosophila melanogaster. Proceedings of the National Academy of Sciences of the United States of America 45 35091469
2017 The histone deacetylase SIRT6 blocks myostatin expression and development of muscle atrophy. Scientific reports 42 28928419
2015 SIRT6 protein deacetylase interacts with MYH DNA glycosylase, APE1 endonuclease, and Rad9-Rad1-Hus1 checkpoint clamp. BMC molecular biology 41 26063178
2021 SIRT6 controls hepatic lipogenesis by suppressing LXR, ChREBP, and SREBP1. Biochimica et biophysica acta. Molecular basis of disease 40 34425214
2020 FOXO3a‑SIRT6 axis suppresses aerobic glycolysis in melanoma. International journal of oncology 40 32124950
2021 SIRT6-CBP-dependent nuclear Tau accumulation and its role in protein synthesis. Cell reports 38 33910019
2015 N-Acylethanolamines Bind to SIRT6. Chembiochem : a European journal of chemical biology 38 26607666
2022 Ginsenoside Rc Modulates SIRT6-NRF2 Interaction to Alleviate Alcoholic Liver Disease. Journal of agricultural and food chemistry 37 36300841
2021 BaZiBuShen alleviates cognitive deficits and regulates Sirt6/NRF2/HO-1 and Sirt6/P53-PGC-1α-TERT signaling pathways in aging mice. Journal of ethnopharmacology 37 34547420
2015 SIRT6 deficiency culminates in low-turnover osteopenia. Bone 37 26189760
2020 SIRT6-PARP1 is involved in HMGB1 polyADP-ribosylation and acetylation and promotes chemotherapy-induced autophagy in leukemia. Cancer biology & therapy 36 31928132
2023 SIRT6 is an epigenetic repressor of thoracic aortic aneurysms via inhibiting inflammation and senescence. Signal transduction and targeted therapy 35 37394473
2017 SIRT6 inhibits growth of gastric cancer by inhibiting JAK2/STAT3 pathway. Oncology reports 35 28656307
2023 Overexpressed SIRT6 ameliorates doxorubicin-induced cardiotoxicity and potentiates the therapeutic efficacy through metabolic remodeling. Acta pharmaceutica Sinica. B 33 37425037
2022 Inhibition of AKT induces p53/SIRT6/PARP1-dependent parthanatos to suppress tumor growth. Cell communication and signaling : CCS 33 35715817
2019 SIRT6 Suppresses NFATc4 Expression and Activation in Cardiomyocyte Hypertrophy. Frontiers in pharmacology 33 30670969
2016 Sirt6 regulates dendritic cell differentiation, maturation, and function. Aging 33 26761436
2022 Oleanolic acid induces HCT116 colon cancer cell death through the p38/FOXO3a/Sirt6 pathway. Chemico-biological interactions 31 35690101
2024 USP18 Stabilized FTO Protein to Activate Mitophagy in Ischemic Stroke Through Repressing m6A Modification of SIRT6. Molecular neurobiology 30 38340205
2024 Sirt6 overexpression relieves ferroptosis and delays the progression of diabetic nephropathy via Nrf2/GPX4 pathway. Renal failure 30 39082470
2024 Discovery of Novel PROTAC SIRT6 Degraders with Potent Efficacy against Hepatocellular Carcinoma. Journal of medicinal chemistry 30 39323022
2022 SIRT6 promotes mitochondrial fission and subsequent cellular invasion in ovarian cancer. FEBS open bio 30 35686673
2022 SIRT6 Prevents Glucocorticoid-Induced Osteonecrosis of the Femoral Head in Rats. Oxidative medicine and cellular longevity 30 36275897
2018 PKCζ Phosphorylates SIRT6 to Mediate Fatty Acid β-Oxidation in Colon Cancer Cells. Neoplasia (New York, N.Y.) 30 30504065
2018 SIRT6 inhibits colorectal cancer stem cell proliferation by targeting CDC25A. Oncology letters 29 29552180
2023 SIRT6 drives sensitivity to ferroptosis in anaplastic thyroid cancer through NCOA4-dependent autophagy. American journal of cancer research 28 36895980
2022 Sirt6 deficiency contributes to mitochondrial fission and oxidative damage in podocytes via ROCK1-Drp1 signalling pathway. Cell proliferation 25 35842903
2024 Specnuezhenide ameliorates hepatic fibrosis via regulating SIRT6-Mediated inflammatory signaling cascades. Journal of ethnopharmacology 24 39097210
2022 The role of Sirt6 in osteoarthritis and its effect on macrophage polarization. Bioengineered 24 35443857
2022 Hepatic SIRT6 Modulates Transcriptional Activities of FXR to Alleviate Acetaminophen-induced Hepatotoxicity. Cellular and molecular gastroenterology and hepatology 24 35526796
2020 ERRγ suppression by Sirt6 alleviates cholestatic liver injury and fibrosis. JCI insight 24 32701506
2018 Hepatocyte-specific Sirt6 deficiency impairs ketogenesis. The Journal of biological chemistry 24 30530497
2022 SIRT6 promotes ferroptosis and attenuates glycolysis in pancreatic cancer through regulation of the NF-κB pathway. Experimental and therapeutic medicine 23 35837046
2019 Sirtuins and SIRT6 in Carcinogenesis and in Diet. International journal of molecular sciences 22 31591350
2022 NMN ameliorated radiation induced damage in NRF2-deficient cell and mice via regulating SIRT6 and SIRT7. Free radical biology & medicine 21 36252808
2023 Hesperetin attenuates cognitive dysfunction via SIRT6/NLRP3 pathway in scopolamine-induced mice. Metabolic brain disease 20 37382831
2022 Sirt6 mediates antioxidative functions by increasing Nrf2 abundance. Experimental cell research 20 36356655
2022 Modulation of SIRT6 activity acts as an emerging therapeutic implication for pathological disorders in the skeletal system. Genes & diseases 20 37396554
2021 SIRT6 Through the Brain Evolution, Development, and Aging. Frontiers in aging neuroscience 20 34720996
2023 SIRT6 promotes metastasis and relapse in HER2-positive breast cancer. Scientific reports 19 38081972
2020 Activation of SIRT6 by DNA hypomethylating agents and clinical consequences on combination therapy in leukemia. Scientific reports 19 32587297
2017 Sirt6 alters adult hippocampal neurogenesis. PloS one 19 28644902
2024 SIRT6 activates PPARα to improve doxorubicin-induced myocardial cell aging and damage. Chemico-biological interactions 18 38395252
2024 Sirt6 protects retinal ganglion cells and optic nerve from degeneration during aging and glaucoma. Molecular therapy : the journal of the American Society of Gene Therapy 18 38659223
2023 SIRT6: A potential therapeutic target for diabetic cardiomyopathy. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 18 37462453
2022 SIRT6 stabilization and cytoplasmic localization in macrophages regulates acute and chronic inflammation in mice. The Journal of biological chemistry 18 35150745
2022 Downregulation of Sirt6 by CD38 promotes cell senescence and aging. Aging 18 36490326
2024 Binding to nucleosome poises human SIRT6 for histone H3 deacetylation. eLife 17 38415718
2021 SIRT6 regulates SREBP1c-induced glucolipid metabolism in liver and pancreas via the AMPKα-mTORC1 pathway. Laboratory investigation; a journal of technical methods and pathology 17 34923569
2018 Scientometric Analysis of SIRT6 Studies. Medical science monitor : international medical journal of experimental and clinical research 17 30457131
2023 SIRT6's function in controlling the metabolism of lipids and glucose in diabetic nephropathy. Frontiers in endocrinology 16 37876546
2019 Cumulus cell-derived and maternal SIRT6 differentially regulates porcine oocyte meiotic maturation. Theriogenology 16 31593883
2020 Is nuclear sirtuin SIRT6 a master regulator of immune function? American journal of physiology. Endocrinology and metabolism 15 33308014
2017 SIRT6 regulated nucleosomal occupancy affects Hexokinase 2 expression. Experimental cell research 15 28478957
2025 The Role and Molecular Pathways of SIRT6 in Senescence and Age-related Diseases. Advanced biology 14 39913122
2022 Endothelial SIRT6 deficiency promotes arterial thrombosis in mice. Journal of molecular and cellular cardiology 14 36414111

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