{"gene":"SIRT6","run_date":"2026-06-10T07:46:32","timeline":{"discoveries":[{"year":2011,"finding":"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.","method":"Co-immunoprecipitation, in vitro mono-ADP-ribosylation assay, site-directed mutagenesis (K521), DSB repair assays in mammalian cells under oxidative stress","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay with specific mutagenesis (K521) plus cellular DSB repair assays; replicated conceptually in multiple subsequent studies","pmids":["21680843"],"is_preprint":false},{"year":2019,"finding":"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.","method":"SIRT6 knockout mouse model, siRNA knockdown, NRTI treatment, cytoplasmic L1 cDNA quantification, interferon response measurement, cGAS pathway analysis","journal":"Cell Metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO combined with pharmacological rescue (NRTIs) and siRNA, multiple orthogonal readouts across in vivo and in vitro systems","pmids":["30853213"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Co-immunoprecipitation, chromatin fractionation, SIRT6 enzymatic assays, lamin A/progerin overexpression and knockdown, DNA damage response readouts (DNA-PKcs recruitment, CtIP deacetylation)","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, multiple functional endpoints (chromatin localization, substrate deacetylation, PARP1 ribosylation), gain- and loss-of-function experiments in one study","pmids":["26549451"],"is_preprint":false},{"year":2020,"finding":"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.","method":"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","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — direct in vitro DNA-binding characterization combined with cellular epistasis experiments and multiple DDR readouts in one rigorous study","pmids":["31995034"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, live-cell imaging of CHD4 recruitment, HR assays, SIRT6/CHD4 knockdown with DNA repair readouts, ATM inhibition epistasis","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional HR assays and epistasis with ATM, multiple orthogonal approaches in one study","pmids":["31970415"],"is_preprint":false},{"year":2017,"finding":"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.","method":"SIRT6 knockout MEFs, in vitro defatty-acylation assay, subcellular fractionation, co-immunoprecipitation (R-Ras2/PI3K), Akt phosphorylation readout, cell proliferation assay","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro enzymatic deacylation assay combined with KO cellular studies and multiple downstream readouts (localization, PI3K interaction, Akt activation)","pmids":["28406396"],"is_preprint":false},{"year":2019,"finding":"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.","method":"ChIP, Co-immunoprecipitation, SIRT6 heterozygous and transgenic mouse metabolomics, in vitro deacetylation of NCOA2, gene expression analyses, 13C metabolic tracing","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — ChIP, Co-IP, in vitro deacetylation assay, and in vivo metabolomics in multiple mouse models within one study","pmids":["31851938"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Cryo-EM structure determination, molecular dynamics simulations of histone tails in nucleosome-bound SIRT6 complex","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure with molecular dynamics validation of active-site positioning; single lab but high methodological rigor","pmids":["38415718"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Co-immunoprecipitation (SIRT6-ATF2), ChIP (ATF2 on PGC-1α promoter), adipose-specific SIRT6 KO mice, thermogenic gene expression assays, oxygen consumption measurement","journal":"Cell Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ChIP in adipose-specific KO context, but mechanistic detail of SIRT6's enzymatic role in ATF2 regulation not fully defined","pmids":["28723567"],"is_preprint":false},{"year":2010,"finding":"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.","method":"In vitro deacetylase assays with histone substrates, chromatin immunoprecipitation, genetic deletion models","journal":"Trends in Biochemical Sciences","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — review consolidating multiple in vitro enzymatic assays and ChIP experiments from prior primary literature; not a single primary paper but cites established biochemical work","pmids":["20729089"],"is_preprint":false},{"year":2017,"finding":"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.","method":"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","journal":"Nature Communications","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — specific deacetylation site identified by mass spectrometry and confirmed by mutagenesis, combined with cellular translocation assays and in vivo genetic model","pmids":["36496445"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Co-immunoprecipitation, in vivo deacetylation assays, ubiquitylation assays, TRF2 mutant (TRF2cT) overexpression, SIRT6 knockdown with TRF2 protein stability readout","journal":"Nucleic Acids Research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, in vivo deacetylation, ubiquitylation, and domain-mapping with mutant TRF2 across multiple experiments","pmids":["27923994"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Brain-specific SIRT6 KO mice, Western blotting for phospho-Tau and GSK3 activation, behavioral assays, loss-of-function with defined molecular phenotype","journal":"Cell Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — brain-specific KO with multiple molecular readouts (Tau phosphorylation, GSK3 activation) but limited direct enzymatic assay of SIRT6 on Tau in this paper","pmids":["28355558"],"is_preprint":false},{"year":2021,"finding":"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.","method":"SIRT6 KO cells and neurons, acetylation-mimetic Tau mutants, nuclear fractionation, transcriptomic analysis, immunofluorescence in human AD brain tissue","journal":"Cell Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specific deacetylation site (K174) defined with acetylation-mimetic mutants and nuclear fractionation, corroborated in human AD tissue; single lab","pmids":["33910019"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Co-immunoprecipitation (SIRT6-Pol II, SIRT6-NELF), ChIP-seq for H3K9ac/H3K56ac and elongation factors, CDK9 activity assays, SIRT6 KO transcriptomic analysis","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating SIRT6-Pol II/NELF interaction, ChIP-seq for multiple histone marks, and functional transcription elongation readouts in one study","pmids":["31399344"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Co-immunoprecipitation, pulldown assays, mutagenesis of MYH interdomain connector, live-cell imaging at confined oxidative damage sites, telomere co-localization assays","journal":"BMC Molecular Biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple Co-IPs and pulldowns with mutagenesis, cellular localization studies; single lab","pmids":["26063178"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Co-immunoprecipitation (PKCζ-SIRT6 in vitro and in vivo), site-directed mutagenesis (T294), ChIP on β-oxidation gene promoters, PKCζ kinase assay","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay with specific phosphorylation site (T294), Co-IP, and ChIP; single lab but multiple orthogonal methods","pmids":["30504065"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation (SIRT6-LXRα, SIRT6-ChREBP, SIRT6-SREBP1c), in vitro and in vivo deacetylation assays, liver-specific SIRT6 KO mice on Western diet","journal":"Biochimica et Biophysica Acta – Molecular Basis of Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and deacetylation for three substrates in hepatic KO model; single lab","pmids":["34425214"],"is_preprint":false},{"year":2020,"finding":"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.","method":"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","journal":"JCI Insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo deacetylation with genetic KO/rescue and epistasis experiment (ERRγ KD rescues SIRT6 deficiency); single lab","pmids":["32701506"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Hepatocyte-specific SIRT6 KO mice, in vivo FXR deacetylation assay, FXR KO epistasis, pharmacological SIRT6 activation, RNA-seq","journal":"Cellular and Molecular Gastroenterology and Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo deacetylation with genetic epistasis (FXR KO) and pharmacological rescue; single lab","pmids":["35526796"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Podocyte-specific SIRT6 KO mice in diabetic and adriamycin nephropathy models, ChIP (H3K9ac at Notch promoters), gene expression analysis","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating H3K9 deacetylation at specific Notch promoters combined with podocyte-specific KO models; single lab","pmids":["28871079"],"is_preprint":false},{"year":2018,"finding":"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.","method":"CRISPR-Cas9 SIRT6 KO in cynomolgus monkeys, ChIP for histone acetylation at H19 ICR, CTCF ChIP, H19 expression analysis, human neural progenitor differentiation model","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO in non-human primate with mechanistic ChIP experiments plus validation in human neural progenitor system; rigorous multi-system study","pmids":["30135584"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Co-immunoprecipitation (SIRT6-Runx2, SIRT6-Osx), ChIP for H3K9ac at Dkk1/osteoprotegerin/Runx2/Osx promoters, SIRT6 KO bone phenotype analysis","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ChIP with genetic KO bone phenotype; single lab","pmids":["26189760"],"is_preprint":false},{"year":2017,"finding":"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.","method":"ChIP (NF-κB at Mstn promoter), SIRT6 KO mice, overexpression in C2C12 cells, cancer cachexia in vivo model","journal":"Scientific Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating mechanism at Mstn promoter with genetic KO phenotype; single lab","pmids":["28928419"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Co-immunoprecipitation (SIRT6-Crebh), ChIP (Crebh at Fsp27β promoter), hepatocyte-specific SIRT6 KO mice, Fsp27 siRNA rescue experiment","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ChIP combined with genetic rescue (Fsp27 siRNA); single lab","pmids":["30530497"],"is_preprint":false},{"year":2022,"finding":"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).","method":"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":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — subcellular localization by immunofluorescence linked to TNFα secretion functional readout, confirmed in vivo; single lab, limited direct enzymatic assay of demyristoylation in this paper","pmids":["35150745"],"is_preprint":false},{"year":2016,"finding":"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.","method":"ChIP (SIRT6 and H3K9ac at TNFSF4 promoter), SIRT6 KO endothelial cells and ApoE-/- mice, RNA-seq, monocyte adhesion assays","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating H3K9 deacetylation at TNFSF4 promoter with in vivo KO atherosclerosis model; single lab","pmids":["27249230"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Brain-specific SIRT6 KO transcriptomics and metabolomics, Co-immunoprecipitation (SIRT6-YY1), SIRT3/SIRT4 restoration rescue experiments, mitochondrial functional assays (ROS, membrane potential, mitochondrial number)","journal":"Cell Death & Disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, transcriptomics/metabolomics, and genetic rescue experiments in KO brain; single lab","pmids":["36653345"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Co-immunoprecipitation (SIRT6-NFATc4), adenoviral overexpression of SIRT6 and SIRT6-H133Y, NFATc4 nuclear translocation assays, NFATc4 phosphorylation and acetylation assays, BNP expression readouts","journal":"Frontiers in Pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with catalytic mutant control (H133Y) and NFATc4 translocation assays; single lab","pmids":["30670969"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-immunoprecipitation (SIRT6-PARP1), SIRT6/PARP1 knockdown, HMGB1 ADP-ribosylation and acetylation assays, HMGB1 translocation assays in leukemia cells","journal":"Cancer Biology & Therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and enzymatic assays with knockdown experiments; single lab, limited by abstract detail","pmids":["31928132"],"is_preprint":false},{"year":2023,"finding":"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.","method":"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","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and specific deacetylation site (K192) with in vivo KO model; single lab","pmids":["38135684"],"is_preprint":false},{"year":2023,"finding":"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.","method":"ChIP (SIRT6 and H3K9ac/H3K56ac at Il1b promoter), VSMC-specific SIRT6 KO mice (angiotensin II model), Il1b KO epistasis, anakinra pharmacological rescue","journal":"Signal Transduction and Targeted Therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with two histone marks at Il1b promoter plus genetic and pharmacological epistasis; single lab","pmids":["37394473"],"is_preprint":false},{"year":2022,"finding":"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.","method":"ChIP (H3K9ac at PPARγ promoter), SIRT6 conditional transgenic and KO endothelial mouse models, PPARγ gain-of-function epistasis, endothelial FA uptake assays","journal":"Circulation Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP with conditional mouse models and epistasis; single lab","pmids":["36278398"],"is_preprint":false},{"year":2021,"finding":"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.","method":"SIRT6-transgenic mice (both sexes), 13C lactate tracing, in vivo multi-omics (transcriptomics/metabolomics), gluconeogenic gene expression analysis, NAD+ measurement","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isotope tracing and multi-omics in transgenic model; mechanism upstream of gluconeogenic gene induction not fully defined biochemically","pmids":["34050173"],"is_preprint":false},{"year":2017,"finding":"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.","method":"ChIP for H3K9ac at Notch promoters, podocyte-specific SIRT6 KO in diabetic nephropathy and adriamycin nephropathy mouse models","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-based mechanism with in vivo KO validation; single lab","pmids":["28871079"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Co-immunoprecipitation, GST pulldown (SIRT6-NRF2 interaction), NRF2 protein stability assays in Sirt6+/- MEFs vs. WT, overexpression studies, Keap1-NRF2 interaction assay with SIRT6","journal":"Experimental Cell Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and GST pulldown with protein stability functional assays; single lab","pmids":["36356655"],"is_preprint":false},{"year":2015,"finding":"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.","method":"In vitro SIRT6 deacetylase activity assays with NAEs, quercetin, and luteolin; binding assays; EC50/IC50 determination","journal":"ChemBioChem","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro enzymatic assay with defined pharmacological parameters; single lab, no structural or cellular validation in this paper","pmids":["26607666"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Drosophila dSirt6 characterization (subcellular localization, in vitro HAD assay), overexpression and knockdown lifespan assays, transcriptomics, genetic epistasis with dMyc (haploinsufficiency and OE rescue)","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro enzymatic assay of Drosophila ortholog, genetic epistasis with dMyc; ortholog study, single lab","pmids":["35091469"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Brain-specific SIRT6 KO mice, Western blotting for phospho-Tau and GSK3 activity, behavioral tests, immunofluorescence for DNA damage markers","journal":"Cell Reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — well-defined brain-specific KO with clear molecular pathway (GSK3→Tau phosphorylation) and behavioral/cellular phenotypes; single lab","pmids":["28355558"],"is_preprint":false},{"year":2023,"finding":"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.","method":"SIRT6 overexpression and KO in thyroid cancer cells, ferroptosis inducers (RSL3, erastin), NCOA4-dependent ferritinophagy assays, flow cytometry (cell death/lipid peroxidation)","journal":"American Journal of Cancer Research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — cellular loss/gain-of-function with ferritinophagy readout; mechanistic link between SIRT6 enzymatic activity and NCOA4/ferritin pathway not biochemically established in this abstract","pmids":["36895980"],"is_preprint":false},{"year":2022,"finding":"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.","method":"SIRT6 siRNA knockdown and overexpression in ovarian cancer cells, ERK1/2 phosphorylation assays, DRP1 pS616 measurement, mitochondrial morphology analysis, invasion assays","journal":"FEBS Open Bio","confidence":"Low","confidence_rationale":"Tier 3 / Weak — cellular loss/gain-of-function with pathway readouts but the direct biochemical link between SIRT6 and ERK1/2-DRP1 is not established mechanistically (no Co-IP or direct substrate assay)","pmids":["35686673"],"is_preprint":false},{"year":2021,"finding":"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.","method":"ChIP and luciferase assays (FOXO3a at SIRT6 promoter), lentiviral SIRT6 overexpression/knockdown to rescue FOXO3a effects, glucose/lactate assays, Seahorse flux assay, tumor xenograft","journal":"International Journal of Oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — ChIP/luciferase for transcriptional regulation only (not direct SIRT6 enzymatic mechanism on glycolysis); single lab, limited mechanistic biochemistry","pmids":["32124950"],"is_preprint":false}],"current_model":"SIRT6 is a nuclear NAD+-dependent enzyme with three biochemically distinct activities—histone H3K9/K56 deacetylation, long-chain fatty-acyl (deacylation) removal from substrates including R-Ras2 and pro-TNFα, and mono-ADP-ribosylation of PARP1—that together allow it to function as a DSB sensor and DNA repair activator (directly recognizing breaks via a tunnel-like structure, recruiting ATM, and stimulating PARP1 via K521 ribosylation), an epigenetic repressor of metabolic and inflammatory genes (via H3K9/K56 deacetylation at target promoters including TNFSF4, IL-1β, Notch1/4, and CDC25A), a regulator of transcription elongation (by stabilizing NELF on paused Pol II), a metabolic coordinator (activating PPARα/β-oxidation through NCOA2-K780 deacetylation, suppressing lipogenesis via LXRα/ChREBP/SREBP1c deacetylation, controlling gluconeogenesis and ketogenesis through Crebh-Fsp27 and gluconeogenic gene axes), a substrate deacylase that regulates R-Ras2 membrane localization and PI3K/Akt signaling, a repressor of LINE1 retrotransposition that prevents cGAS-mediated interferon responses, and a nucleosome-docking deacetylase whose cryo-EM structure shows its zinc finger binding the nucleosome acidic patch while DNA unwrapping positions its active site over H3 tails."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2010,"claim":"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","pmids":["20729089"],"confidence":"Medium","gaps":["Does not resolve how target specificity at individual promoters is achieved","Non-histone substrates not yet defined"]},{"year":2011,"claim":"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","pmids":["21680843"],"confidence":"High","gaps":["How SIRT6 is recruited to breaks not addressed here","Relative contribution of ribosylation vs deacetylation to repair unquantified"]},{"year":2015,"claim":"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","pmids":["26549451"],"confidence":"High","gaps":["Structural basis of lamin A activation unknown","Whether activation is direct or via cofactor recruitment unclear"]},{"year":2015,"claim":"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","pmids":["26063178"],"confidence":"Medium","gaps":["Enzymatic consequence of these interactions for BER not established","Single-lab interaction data"]},{"year":2017,"claim":"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","pmids":["28406396"],"confidence":"High","gaps":["Scope of acylated substrate repertoire unknown","In vivo relevance in tumor settings not tested here"]},{"year":2017,"claim":"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","pmids":["27923994"],"confidence":"High","gaps":["Ubiquitin ligase responsible not identified","Telomere phenotype consequences not fully mapped"]},{"year":2017,"claim":"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","pmids":["36496445","28723567"],"confidence":"Medium","gaps":["Whether ATF2 is a direct deacetylation substrate not resolved","Tissue specificity of these axes not generalized"]},{"year":2018,"claim":"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","pmids":["30135584"],"confidence":"High","gaps":["Direct demonstration that SIRT6 binds the H19 ICR not shown","Generalizability to other imprinted loci unknown"]},{"year":2018,"claim":"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","pmids":["30504065"],"confidence":"Medium","gaps":["Effect of T294 phosphorylation on enzymatic activity per se not measured","Single cancer cell context"]},{"year":2019,"claim":"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","pmids":["31851938","30853213"],"confidence":"High","gaps":["How SIRT6 silences L1 loci mechanistically not fully defined","Direct vs indirect control of SREBP activity not separated"]},{"year":2019,"claim":"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","pmids":["31399344"],"confidence":"High","gaps":["Whether NELF stabilization is deacetylation-dependent not fully isolated","Genome-wide scope of paused genes regulated unclear"]},{"year":2020,"claim":"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","pmids":["31995034"],"confidence":"High","gaps":["Structural basis of the DNA-binding tunnel not solved","Relationship to lamin A-dependent recruitment unresolved"]},{"year":2020,"claim":"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","pmids":["31970415"],"confidence":"High","gaps":["Order of SIRT6/CHD4/ATM events not fully resolved","Direct CHD4 interaction interface not mapped"]},{"year":2021,"claim":"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","pmids":["34425214","32701506","35526796","30530497","34050173"],"confidence":"Medium","gaps":["Direct deacetylation sites not defined for all factors","Upstream signal integrating these axes biochemically unclear"]},{"year":2021,"claim":"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","pmids":["36653345","36356655"],"confidence":"Medium","gaps":["Whether YY1 or NRF2 are direct enzymatic substrates not established","Single-lab interaction evidence"]},{"year":2024,"claim":"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","pmids":["38415718"],"confidence":"High","gaps":["Structure of SIRT6 engaging DSB DNA or non-histone substrates not solved","How activators like lamin A or NAEs alter this engagement unknown"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[9,5,10,11,28,30,17]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,29]},{"term_id":"GO:0042393","term_label":"histone binding","supporting_discovery_ids":[7,9]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[6,14,26]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[7,9,14]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[3,7,4]},{"term_id":"GO:0005730","term_label":"nucleolus","supporting_discovery_ids":[37]}],"pathway":[{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[0,3,4,2]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[14,26,20,31]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[6,17,33,24]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[7,9,21]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,31,30,25]}],"complexes":[],"partners":["PARP1","CHD4","RNA POL II","NELF","TRF2","STAT5","RORGAMMAT","NCOA2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N6T7","full_name":"NAD-dependent protein deacylase sirtuin-6","aliases":["NAD-dependent protein deacetylase sirtuin-6","Protein mono-ADP-ribosyltransferase sirtuin-6","Regulatory protein SIR2 homolog 6","hSIRT6","SIR2-like protein 6"],"length_aa":355,"mass_kda":39.1,"function":"NAD-dependent protein deacetylase, deacylase and mono-ADP-ribosyltransferase that plays an essential role in DNA damage repair, telomere maintenance, metabolic homeostasis, inflammation, tumorigenesis and aging (PubMed:18337721, PubMed:19135889, PubMed:19625767, PubMed:21362626, PubMed:21680843, PubMed:23217706, PubMed:23552949, PubMed:23653361, PubMed:24052263, PubMed:27180906, PubMed:27322069, PubMed:29555651, PubMed:30374165). Displays protein-lysine deacetylase or defatty-acylase (demyristoylase and depalmitoylase) activity, depending on the context (PubMed:23552949, PubMed:24052263, PubMed:27322069). Acts as a key histone deacetylase by catalyzing deacetylation of histone H3 at 'Lys-9', 'Lys-18' and 'Lys-56' (H3K9ac, H3K18ac and H3K56ac, respectively), suppressing target gene expression of several transcription factors, including NF-kappa-B (PubMed:19625767, PubMed:21362626, PubMed:23892288, PubMed:23911928, PubMed:24012758, PubMed:26456828, PubMed:26898756, PubMed:27043296, PubMed:27180906, PubMed:30374165, PubMed:33067423). Acts as an inhibitor of transcription elongation by mediating deacetylation of H3K9ac and H3K56ac, preventing release of NELFE from chromatin and causing transcriptional pausing (By similarity). Involved in DNA repair by promoting double-strand break (DSB) repair: acts as a DSB sensor by recognizing and binding DSB sites, leading to (1) recruitment of DNA repair proteins, such as SMARCA5/SNF2H, and (2) deacetylation of histone H3K9ac and H3K56ac (PubMed:23911928, PubMed:31995034, PubMed:32538779). SIRT6 participation to DSB repair is probably involved in extension of life span (By similarity). Also promotes DNA repair by deacetylating non-histone proteins, such as DDB2 and p53/TP53 (PubMed:29474172, PubMed:32789493). Specifically deacetylates H3K18ac at pericentric heterochromatin, thereby maintaining pericentric heterochromatin silencing at centromeres and protecting against genomic instability and cellular senescence (PubMed:27043296). Involved in telomere maintenance by catalyzing deacetylation of histone H3 in telomeric chromatin, regulating telomere position effect and telomere movement in response to DNA damage (PubMed:18337721, PubMed:19625767, PubMed:21847107). Required for embryonic stem cell differentiation by mediating histone deacetylation of H3K9ac (PubMed:25915124, PubMed:29555651). Plays a major role in metabolism by regulating processes such as glycolysis, gluconeogenesis, insulin secretion and lipid metabolism (PubMed:24012758, PubMed:26787900). Inhibits glycolysis via histone deacetylase activity and by acting as a corepressor of the transcription factor HIF1A, thereby controlling the expression of multiple glycolytic genes (By similarity). Has tumor suppressor activity by repressing glycolysis, thereby inhibiting the Warburg effect (PubMed:23217706). Also regulates glycolysis and tumorigenesis by mediating deacetylation and nuclear export of non-histone proteins, such as isoform M2 of PKM (PKM2) (PubMed:26787900). Acts as a negative regulator of gluconeogenesis by mediating deacetylation of non-histone proteins, such as FOXO1 and KAT2A/GCN5 (PubMed:23142079, PubMed:25009184). Promotes beta-oxidation of fatty acids during fasting by catalyzing deacetylation of NCOA2, inducing coactivation of PPARA (By similarity). Acts as a regulator of lipid catabolism in brown adipocytes, both by catalyzing deacetylation of histones and non-histone proteins, such as FOXO1 (By similarity). Also acts as a regulator of circadian rhythms, both by regulating expression of clock-controlled genes involved in lipid and carbohydrate metabolism, and by catalyzing deacetylation of PER2 (By similarity). The defatty-acylase activity is specifically involved in regulation of protein secretion (PubMed:23552949, PubMed:24052263, PubMed:27322069, PubMed:28406396). Has high activity toward long-chain fatty acyl groups and mediates protein-lysine demyristoylation and depalmitoylation of target proteins, such as RRAS2 and TNF, thereby regulating their secretion (PubMed:23552949, PubMed:28406396). Also acts as a mono-ADP-ribosyltransferase by mediating mono-ADP-ribosylation of PARP1, TRIM28/KAP1 or SMARCC2/BAF170 (PubMed:21680843, PubMed:22753495, PubMed:27322069, PubMed:27568560). Mono-ADP-ribosyltransferase activity is involved in DNA repair, cellular senescence, repression of LINE-1 retrotransposon elements and regulation of transcription (PubMed:21680843, PubMed:22753495, PubMed:27568560)","subcellular_location":"Nucleus; Chromosome; Chromosome, telomere; Endoplasmic reticulum","url":"https://www.uniprot.org/uniprotkb/Q8N6T7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SIRT6","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SIRT6","total_profiled":1310},"omim":[{"mim_id":"613303","title":"AlkB HOMOLOG 5, RNA DEMETHYLASE; ALKBH5","url":"https://www.omim.org/entry/613303"},{"mim_id":"606212","title":"SIRTUIN 7; SIRT7","url":"https://www.omim.org/entry/606212"},{"mim_id":"606211","title":"SIRTUIN 6; SIRT6","url":"https://www.omim.org/entry/606211"},{"mim_id":"604611","title":"RECQ PROTEIN-LIKE 2; RECQL2","url":"https://www.omim.org/entry/604611"},{"mim_id":"604124","title":"RETINOBLASTOMA-BINDING PROTEIN 8; RBBP8","url":"https://www.omim.org/entry/604124"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SIRT6"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q8N6T7","domains":[{"cath_id":"3.40.50.1220","chopping":"27-134_192-270","consensus_level":"high","plddt":98.0407,"start":27,"end":270},{"cath_id":"2.20.28.200","chopping":"138-185","consensus_level":"medium","plddt":96.4038,"start":138,"end":185}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N6T7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N6T7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N6T7-F1-predicted_aligned_error_v6.png","plddt_mean":87.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SIRT6","jax_strain_url":"https://www.jax.org/strain/search?query=SIRT6"},"sequence":{"accession":"Q8N6T7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N6T7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N6T7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N6T7"}},"corpus_meta":[{"pmid":"21680843","id":"PMC_21680843","title":"SIRT6 promotes DNA repair under stress by activating PARP1.","date":"2011","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/21680843","citation_count":696,"is_preprint":false},{"pmid":"30853213","id":"PMC_30853213","title":"LINE1 Derepression in Aged Wild-Type and SIRT6-Deficient Mice Drives Inflammation.","date":"2019","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/30853213","citation_count":389,"is_preprint":false},{"pmid":"24438746","id":"PMC_24438746","title":"Chromatin and beyond: the multitasking roles for SIRT6.","date":"2014","source":"Trends in biochemical sciences","url":"https://pubmed.ncbi.nlm.nih.gov/24438746","citation_count":299,"is_preprint":false},{"pmid":"28871079","id":"PMC_28871079","title":"Sirt6 deficiency exacerbates podocyte injury and proteinuria through targeting Notch signaling.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28871079","citation_count":291,"is_preprint":false},{"pmid":"27836583","id":"PMC_27836583","title":"SIRT6: Novel Mechanisms and Links to Aging and Disease.","date":"2016","source":"Trends in endocrinology and metabolism: TEM","url":"https://pubmed.ncbi.nlm.nih.gov/27836583","citation_count":215,"is_preprint":false},{"pmid":"33353368","id":"PMC_33353368","title":"SIRT6 Protects Smooth Muscle Cells From Senescence and Reduces Atherosclerosis.","date":"2020","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/33353368","citation_count":203,"is_preprint":false},{"pmid":"31437090","id":"PMC_31437090","title":"SIRT6, a Mammalian Deacylase with Multitasking Abilities.","date":"2019","source":"Physiological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/31437090","citation_count":191,"is_preprint":false},{"pmid":"34050173","id":"PMC_34050173","title":"Restoration of energy homeostasis by SIRT6 extends healthy lifespan.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34050173","citation_count":155,"is_preprint":false},{"pmid":"33325563","id":"PMC_33325563","title":"Emerging roles of SIRT6 in human diseases and its modulators.","date":"2020","source":"Medicinal research reviews","url":"https://pubmed.ncbi.nlm.nih.gov/33325563","citation_count":152,"is_preprint":false},{"pmid":"30135584","id":"PMC_30135584","title":"SIRT6 deficiency results in developmental retardation in cynomolgus monkeys.","date":"2018","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/30135584","citation_count":150,"is_preprint":false},{"pmid":"23514751","id":"PMC_23514751","title":"SIRT6 modulates paclitaxel and epirubicin resistance and survival in breast cancer.","date":"2013","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/23514751","citation_count":134,"is_preprint":false},{"pmid":"36463827","id":"PMC_36463827","title":"Melatonin inhibits ferroptosis and 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SIRT6 is recruited to sites of DSBs and stimulates repair through both NHEJ and HR.\",\n      \"method\": \"Co-immunoprecipitation, in vitro mono-ADP-ribosylation assay, site-directed mutagenesis (K521), DSB repair assays in mammalian cells under oxidative stress\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay with specific mutagenesis (K521) plus cellular DSB repair assays; replicated conceptually in multiple subsequent studies\",\n      \"pmids\": [\"21680843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"SIRT6 knockout mouse model, siRNA knockdown, NRTI treatment, cytoplasmic L1 cDNA quantification, interferon response measurement, cGAS pathway analysis\",\n      \"journal\": \"Cell Metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO combined with pharmacological rescue (NRTIs) and siRNA, multiple orthogonal readouts across in vivo and in vitro systems\",\n      \"pmids\": [\"30853213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, chromatin fractionation, SIRT6 enzymatic assays, lamin A/progerin overexpression and knockdown, DNA damage response readouts (DNA-PKcs recruitment, CtIP deacetylation)\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, multiple functional endpoints (chromatin localization, substrate deacetylation, PARP1 ribosylation), gain- and loss-of-function experiments in one study\",\n      \"pmids\": [\"26549451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct in vitro DNA-binding characterization combined with cellular epistasis experiments and multiple DDR readouts in one rigorous study\",\n      \"pmids\": [\"31995034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, live-cell imaging of CHD4 recruitment, HR assays, SIRT6/CHD4 knockdown with DNA repair readouts, ATM inhibition epistasis\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional HR assays and epistasis with ATM, multiple orthogonal approaches in one study\",\n      \"pmids\": [\"31970415\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"SIRT6 knockout MEFs, in vitro defatty-acylation assay, subcellular fractionation, co-immunoprecipitation (R-Ras2/PI3K), Akt phosphorylation readout, cell proliferation assay\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro enzymatic deacylation assay combined with KO cellular studies and multiple downstream readouts (localization, PI3K interaction, Akt activation)\",\n      \"pmids\": [\"28406396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP, Co-immunoprecipitation, SIRT6 heterozygous and transgenic mouse metabolomics, in vitro deacetylation of NCOA2, gene expression analyses, 13C metabolic tracing\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — ChIP, Co-IP, in vitro deacetylation assay, and in vivo metabolomics in multiple mouse models within one study\",\n      \"pmids\": [\"31851938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Cryo-EM structure determination, molecular dynamics simulations of histone tails in nucleosome-bound SIRT6 complex\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure with molecular dynamics validation of active-site positioning; single lab but high methodological rigor\",\n      \"pmids\": [\"38415718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (SIRT6-ATF2), ChIP (ATF2 on PGC-1α promoter), adipose-specific SIRT6 KO mice, thermogenic gene expression assays, oxygen consumption measurement\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ChIP in adipose-specific KO context, but mechanistic detail of SIRT6's enzymatic role in ATF2 regulation not fully defined\",\n      \"pmids\": [\"28723567\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro deacetylase assays with histone substrates, chromatin immunoprecipitation, genetic deletion models\",\n      \"journal\": \"Trends in Biochemical Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — review consolidating multiple in vitro enzymatic assays and ChIP experiments from prior primary literature; not a single primary paper but cites established biochemical work\",\n      \"pmids\": [\"20729089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — specific deacetylation site identified by mass spectrometry and confirmed by mutagenesis, combined with cellular translocation assays and in vivo genetic model\",\n      \"pmids\": [\"36496445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vivo deacetylation assays, ubiquitylation assays, TRF2 mutant (TRF2cT) overexpression, SIRT6 knockdown with TRF2 protein stability readout\",\n      \"journal\": \"Nucleic Acids Research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, in vivo deacetylation, ubiquitylation, and domain-mapping with mutant TRF2 across multiple experiments\",\n      \"pmids\": [\"27923994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Brain-specific SIRT6 KO mice, Western blotting for phospho-Tau and GSK3 activation, behavioral assays, loss-of-function with defined molecular phenotype\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — brain-specific KO with multiple molecular readouts (Tau phosphorylation, GSK3 activation) but limited direct enzymatic assay of SIRT6 on Tau in this paper\",\n      \"pmids\": [\"28355558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"SIRT6 KO cells and neurons, acetylation-mimetic Tau mutants, nuclear fractionation, transcriptomic analysis, immunofluorescence in human AD brain tissue\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specific deacetylation site (K174) defined with acetylation-mimetic mutants and nuclear fractionation, corroborated in human AD tissue; single lab\",\n      \"pmids\": [\"33910019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (SIRT6-Pol II, SIRT6-NELF), ChIP-seq for H3K9ac/H3K56ac and elongation factors, CDK9 activity assays, SIRT6 KO transcriptomic analysis\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating SIRT6-Pol II/NELF interaction, ChIP-seq for multiple histone marks, and functional transcription elongation readouts in one study\",\n      \"pmids\": [\"31399344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, pulldown assays, mutagenesis of MYH interdomain connector, live-cell imaging at confined oxidative damage sites, telomere co-localization assays\",\n      \"journal\": \"BMC Molecular Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple Co-IPs and pulldowns with mutagenesis, cellular localization studies; single lab\",\n      \"pmids\": [\"26063178\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (PKCζ-SIRT6 in vitro and in vivo), site-directed mutagenesis (T294), ChIP on β-oxidation gene promoters, PKCζ kinase assay\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay with specific phosphorylation site (T294), Co-IP, and ChIP; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"30504065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (SIRT6-LXRα, SIRT6-ChREBP, SIRT6-SREBP1c), in vitro and in vivo deacetylation assays, liver-specific SIRT6 KO mice on Western diet\",\n      \"journal\": \"Biochimica et Biophysica Acta – Molecular Basis of Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and deacetylation for three substrates in hepatic KO model; single lab\",\n      \"pmids\": [\"34425214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"JCI Insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo deacetylation with genetic KO/rescue and epistasis experiment (ERRγ KD rescues SIRT6 deficiency); single lab\",\n      \"pmids\": [\"32701506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Hepatocyte-specific SIRT6 KO mice, in vivo FXR deacetylation assay, FXR KO epistasis, pharmacological SIRT6 activation, RNA-seq\",\n      \"journal\": \"Cellular and Molecular Gastroenterology and Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo deacetylation with genetic epistasis (FXR KO) and pharmacological rescue; single lab\",\n      \"pmids\": [\"35526796\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Podocyte-specific SIRT6 KO mice in diabetic and adriamycin nephropathy models, ChIP (H3K9ac at Notch promoters), gene expression analysis\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating H3K9 deacetylation at specific Notch promoters combined with podocyte-specific KO models; single lab\",\n      \"pmids\": [\"28871079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"CRISPR-Cas9 SIRT6 KO in cynomolgus monkeys, ChIP for histone acetylation at H19 ICR, CTCF ChIP, H19 expression analysis, human neural progenitor differentiation model\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO in non-human primate with mechanistic ChIP experiments plus validation in human neural progenitor system; rigorous multi-system study\",\n      \"pmids\": [\"30135584\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (SIRT6-Runx2, SIRT6-Osx), ChIP for H3K9ac at Dkk1/osteoprotegerin/Runx2/Osx promoters, SIRT6 KO bone phenotype analysis\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ChIP with genetic KO bone phenotype; single lab\",\n      \"pmids\": [\"26189760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP (NF-κB at Mstn promoter), SIRT6 KO mice, overexpression in C2C12 cells, cancer cachexia in vivo model\",\n      \"journal\": \"Scientific Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating mechanism at Mstn promoter with genetic KO phenotype; single lab\",\n      \"pmids\": [\"28928419\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (SIRT6-Crebh), ChIP (Crebh at Fsp27β promoter), hepatocyte-specific SIRT6 KO mice, Fsp27 siRNA rescue experiment\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ChIP combined with genetic rescue (Fsp27 siRNA); single lab\",\n      \"pmids\": [\"30530497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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).\",\n      \"method\": \"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\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — subcellular localization by immunofluorescence linked to TNFα secretion functional readout, confirmed in vivo; single lab, limited direct enzymatic assay of demyristoylation in this paper\",\n      \"pmids\": [\"35150745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP (SIRT6 and H3K9ac at TNFSF4 promoter), SIRT6 KO endothelial cells and ApoE-/- mice, RNA-seq, monocyte adhesion assays\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating H3K9 deacetylation at TNFSF4 promoter with in vivo KO atherosclerosis model; single lab\",\n      \"pmids\": [\"27249230\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Brain-specific SIRT6 KO transcriptomics and metabolomics, Co-immunoprecipitation (SIRT6-YY1), SIRT3/SIRT4 restoration rescue experiments, mitochondrial functional assays (ROS, membrane potential, mitochondrial number)\",\n      \"journal\": \"Cell Death & Disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, transcriptomics/metabolomics, and genetic rescue experiments in KO brain; single lab\",\n      \"pmids\": [\"36653345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (SIRT6-NFATc4), adenoviral overexpression of SIRT6 and SIRT6-H133Y, NFATc4 nuclear translocation assays, NFATc4 phosphorylation and acetylation assays, BNP expression readouts\",\n      \"journal\": \"Frontiers in Pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with catalytic mutant control (H133Y) and NFATc4 translocation assays; single lab\",\n      \"pmids\": [\"30670969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (SIRT6-PARP1), SIRT6/PARP1 knockdown, HMGB1 ADP-ribosylation and acetylation assays, HMGB1 translocation assays in leukemia cells\",\n      \"journal\": \"Cancer Biology & Therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and enzymatic assays with knockdown experiments; single lab, limited by abstract detail\",\n      \"pmids\": [\"31928132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and specific deacetylation site (K192) with in vivo KO model; single lab\",\n      \"pmids\": [\"38135684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP (SIRT6 and H3K9ac/H3K56ac at Il1b promoter), VSMC-specific SIRT6 KO mice (angiotensin II model), Il1b KO epistasis, anakinra pharmacological rescue\",\n      \"journal\": \"Signal Transduction and Targeted Therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with two histone marks at Il1b promoter plus genetic and pharmacological epistasis; single lab\",\n      \"pmids\": [\"37394473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP (H3K9ac at PPARγ promoter), SIRT6 conditional transgenic and KO endothelial mouse models, PPARγ gain-of-function epistasis, endothelial FA uptake assays\",\n      \"journal\": \"Circulation Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP with conditional mouse models and epistasis; single lab\",\n      \"pmids\": [\"36278398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"SIRT6-transgenic mice (both sexes), 13C lactate tracing, in vivo multi-omics (transcriptomics/metabolomics), gluconeogenic gene expression analysis, NAD+ measurement\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isotope tracing and multi-omics in transgenic model; mechanism upstream of gluconeogenic gene induction not fully defined biochemically\",\n      \"pmids\": [\"34050173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP for H3K9ac at Notch promoters, podocyte-specific SIRT6 KO in diabetic nephropathy and adriamycin nephropathy mouse models\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-based mechanism with in vivo KO validation; single lab\",\n      \"pmids\": [\"28871079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown (SIRT6-NRF2 interaction), NRF2 protein stability assays in Sirt6+/- MEFs vs. WT, overexpression studies, Keap1-NRF2 interaction assay with SIRT6\",\n      \"journal\": \"Experimental Cell Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and GST pulldown with protein stability functional assays; single lab\",\n      \"pmids\": [\"36356655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro SIRT6 deacetylase activity assays with NAEs, quercetin, and luteolin; binding assays; EC50/IC50 determination\",\n      \"journal\": \"ChemBioChem\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro enzymatic assay with defined pharmacological parameters; single lab, no structural or cellular validation in this paper\",\n      \"pmids\": [\"26607666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Drosophila dSirt6 characterization (subcellular localization, in vitro HAD assay), overexpression and knockdown lifespan assays, transcriptomics, genetic epistasis with dMyc (haploinsufficiency and OE rescue)\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro enzymatic assay of Drosophila ortholog, genetic epistasis with dMyc; ortholog study, single lab\",\n      \"pmids\": [\"35091469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Brain-specific SIRT6 KO mice, Western blotting for phospho-Tau and GSK3 activity, behavioral tests, immunofluorescence for DNA damage markers\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — well-defined brain-specific KO with clear molecular pathway (GSK3→Tau phosphorylation) and behavioral/cellular phenotypes; single lab\",\n      \"pmids\": [\"28355558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"SIRT6 overexpression and KO in thyroid cancer cells, ferroptosis inducers (RSL3, erastin), NCOA4-dependent ferritinophagy assays, flow cytometry (cell death/lipid peroxidation)\",\n      \"journal\": \"American Journal of Cancer Research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — cellular loss/gain-of-function with ferritinophagy readout; mechanistic link between SIRT6 enzymatic activity and NCOA4/ferritin pathway not biochemically established in this abstract\",\n      \"pmids\": [\"36895980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"SIRT6 siRNA knockdown and overexpression in ovarian cancer cells, ERK1/2 phosphorylation assays, DRP1 pS616 measurement, mitochondrial morphology analysis, invasion assays\",\n      \"journal\": \"FEBS Open Bio\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — cellular loss/gain-of-function with pathway readouts but the direct biochemical link between SIRT6 and ERK1/2-DRP1 is not established mechanistically (no Co-IP or direct substrate assay)\",\n      \"pmids\": [\"35686673\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP and luciferase assays (FOXO3a at SIRT6 promoter), lentiviral SIRT6 overexpression/knockdown to rescue FOXO3a effects, glucose/lactate assays, Seahorse flux assay, tumor xenograft\",\n      \"journal\": \"International Journal of Oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — ChIP/luciferase for transcriptional regulation only (not direct SIRT6 enzymatic mechanism on glycolysis); single lab, limited mechanistic biochemistry\",\n      \"pmids\": [\"32124950\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SIRT6 is a nuclear NAD+-dependent enzyme with three biochemically distinct activities—histone H3K9/K56 deacetylation, long-chain fatty-acyl (deacylation) removal from substrates including R-Ras2 and pro-TNFα, and mono-ADP-ribosylation of PARP1—that together allow it to function as a DSB sensor and DNA repair activator (directly recognizing breaks via a tunnel-like structure, recruiting ATM, and stimulating PARP1 via K521 ribosylation), an epigenetic repressor of metabolic and inflammatory genes (via H3K9/K56 deacetylation at target promoters including TNFSF4, IL-1β, Notch1/4, and CDC25A), a regulator of transcription elongation (by stabilizing NELF on paused Pol II), a metabolic coordinator (activating PPARα/β-oxidation through NCOA2-K780 deacetylation, suppressing lipogenesis via LXRα/ChREBP/SREBP1c deacetylation, controlling gluconeogenesis and ketogenesis through Crebh-Fsp27 and gluconeogenic gene axes), a substrate deacylase that regulates R-Ras2 membrane localization and PI3K/Akt signaling, a repressor of LINE1 retrotransposition that prevents cGAS-mediated interferon responses, and a nucleosome-docking deacetylase whose cryo-EM structure shows its zinc finger binding the nucleosome acidic patch while DNA unwrapping positions its active site over H3 tails.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SIRT6 is a nuclear, chromatin-associated NAD+-dependent enzyme that couples DNA-damage sensing, chromatin-based transcriptional repression, and metabolic control [#9, #3, #6]. 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 [#7, #9]. 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 [#3]; 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 [#0, #4], with chromatin loading promoted by lamin A [#2]. 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 [#5], deacetylates transcription factors and coactivators including NCOA2-K780 to activate PPARalpha-driven beta-oxidation while suppressing lipogenic LXRalpha/ChREBP/SREBP1c programs [#6, #17], and deacetylates substrates such as TRF2, STAT5, NFATc4, and RORgammat to regulate telomere protein turnover, cytokine signaling, cardiomyocyte hypertrophy, and IL-17A transcription [#11, #10, #28, #30]. 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 [#26, #31, #34], and it restrains transcriptional elongation by binding RNA Pol II and stabilizing promoter-proximal NELF pausing [#14]. SIRT6 also represses LINE1 retrotransposition, preventing cytoplasmic L1 cDNA from activating cGAS-driven interferon responses [#1]. These activities integrate into organism-level roles in hepatic lipid and glucose metabolism, adipose thermogenesis, and lifespan extension [#24, #33, #8].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro deacetylase assays with histone substrates, ChIP, and genetic deletion models consolidated in review\",\n      \"pmids\": [\"20729089\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not resolve how target specificity at individual promoters is achieved\", \"Non-histone substrates not yet defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Discovery that SIRT6 mono-ADP-ribosylates PARP1 at K521 showed it stimulates DSB repair through a second, non-deacetylase enzymatic activity beyond histone deacetylation.\",\n      \"evidence\": \"Co-IP, in vitro mono-ADP-ribosylation assay, K521 mutagenesis, and DSB repair assays under oxidative stress\",\n      \"pmids\": [\"21680843\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SIRT6 is recruited to breaks not addressed here\", \"Relative contribution of ribosylation vs deacetylation to repair unquantified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of lamin A as an endogenous activator linked nuclear architecture to SIRT6 chromatin loading and DDR function, and connected progerin to impaired repair.\",\n      \"evidence\": \"Reciprocal Co-IP, chromatin fractionation, SIRT6 enzymatic assays with lamin A/progerin manipulation and DDR readouts\",\n      \"pmids\": [\"26549451\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of lamin A activation unknown\", \"Whether activation is direct or via cofactor recruitment unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"SIRT6 interactions with the BER enzymes MYH/APE1 and the 9-1-1 clamp connected it to oxidative DNA damage processing in active chromatin.\",\n      \"evidence\": \"Co-IP, pulldown assays, MYH interdomain mutagenesis, and live-cell imaging at oxidative damage sites\",\n      \"pmids\": [\"26063178\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Enzymatic consequence of these interactions for BER not established\", \"Single-lab interaction data\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstration that SIRT6 defatty-acylates R-Ras2 established a deacylase activity controlling GTPase membrane localization and PI3K/Akt signaling, extending SIRT6 substrates beyond histones.\",\n      \"evidence\": \"SIRT6 KO MEFs, in vitro defatty-acylation assay, fractionation, R-Ras2/PI3K Co-IP, and Akt/proliferation readouts\",\n      \"pmids\": [\"28406396\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Scope of acylated substrate repertoire unknown\", \"In vivo relevance in tumor settings not tested here\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"SIRT6 deacetylation of the TRF2 TRFH domain triggering its ubiquitin-dependent degradation linked SIRT6 to telomere protein turnover under replication stress.\",\n      \"evidence\": \"Reciprocal Co-IP, in vivo deacetylation, ubiquitylation assays, and TRF2 domain-mapping mutants\",\n      \"pmids\": [\"27923994\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ubiquitin ligase responsible not identified\", \"Telomere phenotype consequences not fully mapped\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Multiple studies extended SIRT6 to non-histone substrate deacetylation in signaling — STAT5-K163 in chondrocytes and PGC-1alpha activation via ATF2 in adipose thermogenesis.\",\n      \"evidence\": \"Co-IP, MS site identification, K163R mutagenesis, ChIP, and tissue-specific KO mice\",\n      \"pmids\": [\"36496445\", \"28723567\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ATF2 is a direct deacetylation substrate not resolved\", \"Tissue specificity of these axes not generalized\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"CRISPR-Cas9 KO in cynomolgus monkey, ChIP for histone acetylation and CTCF, and human neural progenitor validation\",\n      \"pmids\": [\"30135584\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration that SIRT6 binds the H19 ICR not shown\", \"Generalizability to other imprinted loci unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Phosphorylation of SIRT6 at T294 by PKCzeta defined a post-translational mechanism stimulating SIRT6 chromatin enrichment and beta-oxidation gene activation.\",\n      \"evidence\": \"In vitro kinase assay, T294 mutagenesis, Co-IP, and ChIP at beta-oxidation promoters\",\n      \"pmids\": [\"30504065\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effect of T294 phosphorylation on enzymatic activity per se not measured\", \"Single cancer cell context\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"evidence\": \"ChIP, Co-IP, in vitro NCOA2 deacetylation, mouse metabolomics with 13C tracing; KO mice with NRTI rescue and L1 cDNA/interferon readouts\",\n      \"pmids\": [\"31851938\", \"30853213\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SIRT6 silences L1 loci mechanistically not fully defined\", \"Direct vs indirect control of SREBP activity not separated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Discovery that SIRT6 stabilizes NELF-mediated Pol II pausing established a role in restraining transcriptional elongation, mechanistically linking H3K9ac/H3K56ac removal to elongation control.\",\n      \"evidence\": \"Co-IP of SIRT6 with Pol II and NELF, ChIP-seq for histone marks and elongation factors, CDK9 activity assays\",\n      \"pmids\": [\"31399344\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether NELF stabilization is deacetylation-dependent not fully isolated\", \"Genome-wide scope of paused genes regulated unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro DNA-binding assays comparing DSB vs intact DNA, live-cell laser-damage imaging, epistasis with DDR sensors\",\n      \"pmids\": [\"31995034\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the DNA-binding tunnel not solved\", \"Relationship to lamin A-dependent recruitment unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"SIRT6 recruitment of CHD4 to displace HP1 from H3K9me3 defined how it enables HR within compacted, heterochromatic regions in an ATM-dependent manner.\",\n      \"evidence\": \"Reciprocal Co-IP, ChIP, live-cell CHD4 imaging, HR assays, and ATM-inhibition epistasis\",\n      \"pmids\": [\"31970415\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Order of SIRT6/CHD4/ATM events not fully resolved\", \"Direct CHD4 interaction interface not mapped\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP and in vivo deacetylation assays with hepatocyte-specific KO, rescue, and epistasis; transgenic mice with 13C lactate tracing and multi-omics\",\n      \"pmids\": [\"34425214\", \"32701506\", \"35526796\", \"30530497\", \"34050173\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct deacetylation sites not defined for all factors\", \"Upstream signal integrating these axes biochemically unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"SIRT6 was placed in mitochondrial and antioxidant regulation through YY1-dependent control of mitochondrial gene expression and stabilization of NRF2 against Keap1.\",\n      \"evidence\": \"Brain-specific KO transcriptomics/metabolomics with SIRT6-YY1 Co-IP and SIRT3/SIRT4 rescue; Co-IP/GST pulldown with NRF2 stability assays\",\n      \"pmids\": [\"36653345\", \"36356655\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether YY1 or NRF2 are direct enzymatic substrates not established\", \"Single-lab interaction evidence\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Cryo-EM structure determination with molecular dynamics simulation of histone tail positioning\",\n      \"pmids\": [\"38415718\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of SIRT6 engaging DSB DNA or non-histone substrates not solved\", \"How activators like lamin A or NAEs alter this engagement unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [9, 5, 10, 11, 28, 30, 17]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 29]},\n      {\"term_id\": \"GO:0042393\", \"supporting_discovery_ids\": [7, 9]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [6, 14, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [7, 9, 14]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [3, 7, 4]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [37]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [0, 3, 4, 2]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [14, 26, 20, 31]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [6, 17, 33, 24]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [7, 9, 21]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 31, 30, 25]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PARP1\", \"CHD4\", \"RNA Pol II\", \"NELF\", \"TRF2\", \"STAT5\", \"RORgammat\", \"NCOA2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}