SIRT6

This gene encodes a member of the sirtuin family of NAD-dependent enzymes that are implicated in cellular stress resistance, genomic stability, aging and energy homeostasis. The encoded protein is localized to the nucleus, exhibits ADP-ribosyl transferase and histone deacetylase activities, and plays a role in DNA repair, maintenance of telomeric chromatin, inflammation, lipid and glucose metabolism. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]

Sirtuin 6

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:21680843, PubMed:23217706, PubMed:23653361, PubMed:24052263, PubMed:27322069, PubMed:27180906, PubMed:21362626, PubMed:23552949, PubMed:30374165, PubMed:29555651).
Displays protein-lysine deacetylase or defatty-acylase (demyristoylase and depalmitoylase) activity, depending on the context (PubMed:24052263, PubMed:27322069, PubMed:23552949).
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:24012758, PubMed:23892288, PubMed:23911928, PubMed:27043296, PubMed:26898756, PubMed:27180906, PubMed:33067423, PubMed:21362626, PubMed:30374165, PubMed:26456828).
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:32789493, PubMed:29474172).
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:24052263, PubMed:23552949, 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:27568560, PubMed:27322069).
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).

Biological Process base-excision repairIEA:Ensembl
Biological Process cardiac muscle cell differentiationISS:UniProtKB
Biological Process circadian regulation of gene expressionISS:UniProtKB
Biological Process determination of adult lifespanManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process double-strand break repairManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process glucose homeostasisIEA:Ensembl
Biological Process histone H3 deacetylationManual Assertion Based On ExperimentIBA:GO_Central
Biological Process ketone biosynthetic processISS:UniProtKB
Biological Process negative regulation of cell population proliferationIEA:Ensembl
Biological Process negative regulation of cellular senescenceManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process negative regulation of gene expression, epigeneticManual Assertion Based On ExperimentIMP:BHF-UCL
Biological Process negative regulation of gluconeogenesisManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process negative regulation of glucose importIEA:Ensembl
Biological Process negative regulation of glycolytic processManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process negative regulation of protein import into nucleusISS:UniProtKB
Biological Process negative regulation of transcription by RNA polymerase IIISS:UniProtKB
Biological Process negative regulation of transcription elongation by RNA polymerase IIISS:UniProtKB
Biological Process negative regulation of transpositionISS:UniProtKB
Biological Process pericentric heterochromatin assemblyManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process positive regulation of blood vessel branchingManual Assertion Based On ExperimentIMP:BHF-UCL
Biological Process positive regulation of chondrocyte proliferationManual Assertion Based On ExperimentIMP:BHF-UCL
Biological Process positive regulation of cold-induced thermogenesisISS:UniProtKB
Biological Process positive regulation of double-strand break repairManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process positive regulation of fat cell differentiationISS:UniProtKB
Biological Process positive regulation of fibroblast proliferationIEA:Ensembl
Biological Process positive regulation of insulin secretionISS:UniProtKB
Biological Process positive regulation of protein export from nucleusManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process positive regulation of protein localization to chromatinISS:UniProtKB
Biological Process positive regulation of stem cell differentiationISS:UniProtKB
Biological Process positive regulation of stem cell proliferationIEA:Ensembl
Biological Process positive regulation of telomere maintenanceManual Assertion Based On ExperimentIMP:BHF-UCL
Biological Process positive regulation of transcription factor catabolic processManual Assertion Based On ExperimentIMP:CACAO
Biological Process positive regulation of vascular endothelial cell proliferationManual Assertion Based On ExperimentIMP:BHF-UCL
Biological Process protein ADP-ribosylationISS:UniProtKB
Biological Process protein deacetylationManual Assertion Based On ExperimentIMP:CACAO
Biological Process protein delipidationManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process protein destabilizationManual Assertion Based On ExperimentIMP:UniProtKB
Biological Process regulation of circadian rhythmISS:UniProtKB
Biological Process regulation of double-strand break repair via homologous recombinationManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process regulation of lipid catabolic processISS:UniProtKB
Biological Process regulation of lipid metabolic processISS:UniProtKB
Biological Process response to UVManual Assertion Based On ExperimentIDA:UniProtKB
Biological Process subtelomeric heterochromatin assemblyManual Assertion Based On ExperimentIMP:BHF-UCL

Nucleus
Chromosome
Chromosome, telomere
Endoplasmic reticulum
Predominantly nuclear (PubMed:18337721).
Associated with pericentric heterochromatin and telomeric heterochromatin regions (PubMed:18337721, PubMed:27043296).
Localizes to DNA damage sites: directly recognizes and binds double-strand breaks (DSBs) sites via a tunnel-like structure that has high affinity for DSBs (PubMed:21680843, PubMed:23911928, PubMed:27568560, PubMed:31995034, PubMed:32538779).
A fraction localizes to the endoplasmic reticulum (PubMed:23552949).

Acetylated at Lys-33 (PubMed:32538779).
Deacetylation at Lys-33 by SIRT1 promotes homomultimerization and binding to double-strand breaks (DSBs) sites (PubMed:32538779).
Phosphorylation at Ser-10 by MAPK8/JNK1 in response to oxidative stress stimulates the mono-ADP-ribosyltransferase activity on PARP1, leading to PARP1 recruitment to double-strand breaks (DSBs).
Monoubiquitinated at Lys-170 by STUB1/CHIP, preventing its degradation by the proteasome.
Sumoylated, leading to specifically decrease ability to deacetylate histone H3 at 'Lys-56' (H3K56ac).