Sirtuin 6 (SIRT6 or Sirt6) is a stress responsive protein deacetylase and mono-ADP ribosyltransferase enzyme encoded by the SIRT6 gene.^[5][6][7] In laboratory research, SIRT6 appears to function in multiple molecular pathways related to aging, including DNA repair, telomere maintenance, glycolysis and inflammation.^[5] SIRT6 is member of the mammalian sirtuin family of proteins, which are homologs to the yeast Sir2 protein.

Quick Facts SIRT6, Available structures ...

SIRT6
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3K35, 3PKI, 3PKJ, 3ZG6
Identifiers
Aliases	SIRT6, SIR2L6, sirtuin 6
External IDs	OMIM: 606211 MGI: 1354161 HomoloGene: 6924 GeneCards: SIRT6
Gene location (Human) Chr. Chromosome 19 (human)[1] Band 19p13.3 Start 4,174,109 bp[1] End 4,182,566 bp[1]
Gene location (Mouse) Chr. Chromosome 10 (mouse)[2] Band 10 C1|10 39.72 cM Start 81,457,619 bp[2] End 81,463,631 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in anterior pituitary body of pancreas spleen right adrenal gland rectum right lobe of thyroid gland body of stomach monocyte left lobe of thyroid gland skin of abdomen Top expressed in morula neural tube yolk sac blastocyst lip ascending aorta secondary oocyte superior frontal gyrus aortic valve ganglionic eminence More reference expression data BioGPS More reference expression data
Gene ontology Molecular function NAD-dependent histone deacetylase activity transcription corepressor activity protein deacetylase activity zinc ion binding chromatin binding metal ion binding protein binding NAD+ ADP-ribosyltransferase activity hydrolase activity NAD-dependent protein deacetylase activity NAD+ binding NAD+-protein-arginine ADP-ribosyltransferase activity NAD-dependent histone deacetylase activity (H3-K9 specific) histone deacetylase activity Cellular component cytoplasm nucleolus nucleoplasm nucleus Biological process negative regulation of glycolytic process glucose homeostasis regulation of double-strand break repair via homologous recombination positive regulation of fibroblast proliferation protein deacetylation negative regulation of glucose import response to nutrient levels protein destabilization post-embryonic cardiac muscle cell growth involved in heart morphogenesis negative regulation of transcription, DNA-templated positive regulation of stem cell proliferation base-excision repair negative regulation of cell population proliferation histone deacetylation histone H3-K9 modification histone H3-K9 deacetylation protein ADP-ribosylation positive regulation of telomere maintenance positive regulation of chondrocyte proliferation positive regulation of blood vessel branching positive regulation of vascular endothelial cell proliferation positive regulation of cold-induced thermogenesis negative regulation of transcription by RNA polymerase II histone H3 deacetylation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 51548 50721 Ensembl ENSG00000077463 ENSMUSG00000034748 UniProt Q8N6T7 P59941 RefSeq (mRNA) NM_001193285 NM_016539 NM_001321058 NM_001321059 NM_001321060 NM_001321061 NM_001321062 NM_001321063 NM_001321064 NM_001163430 NM_181586 NM_001378944 NM_001378945 RefSeq (protein) NP_001180214 NP_001307987 NP_001307988 NP_001307989 NP_001307990 NP_001307991 NP_001307992 NP_001307993 NP_057623 NP_001156902 NP_853617 NP_001365873 NP_001365874 Location (UCSC) Chr 19: 4.17 – 4.18 Mb Chr 10: 81.46 – 81.46 Mb PubMed search [3] [4]
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Sirt6 is mainly known as a deacetylase of histones H3 and H4, an activity by which it changes chromatin density and regulates gene expression. The enzymatic activity of Sirt6, as well as of the other members of the sirtuins family, is dependent upon the binding of the cofactor nicotinamide adenine dinucleotide (NAD+).^[8]

Mice which have been genetically engineered to overexpress Sirt6 protein exhibit an extended maximum lifespan. This lifespan extension, of about 15–16 percent, is observed only in male mice.^[9]

SIRT6 is a chromatin-associated protein that is required for normal base excision repair and double-strand break repair of DNA damage in mammalian cells.^[10][11] Deficiency of SIRT6 in mice leads to abnormalities that overlap with aging-associated degenerative processes.^[10] A study of 18 species of rodents showed that the longevity of the species was correlated with the efficiency of the SIRT6 enzyme.^[11]

SIRT6 promotes the repair of DNA double-strand breaks by the process of non-homologous end joining and homologous recombination.^[12] SIRT6 stabilizes the repair protein DNA-PKcs (DNA-dependent protein kinase catalytic subunit) at chromatin sites of damage.^[13]

As normal human fibroblasts replicate and progress towards replicative senescence the capability to undergo homologous recombinational repair (HRR) declines.^[14] However, over-expression of SIRT6 in “middle-aged” and pre-senescent cells strongly stimulates HRR.^[14] This effect depends on the mono-ADP ribosylation activity of poly(ADP-ribose) polymerase (PARP1). SIRT6 also rescues the decline in base excision repair of aged human fibroblasts in a PARP1 dependent manner.^[15]

Sirt6 deacetylation activity can be stimulated by high concentrations (several hundred micromolar) of fatty acids,^[16] and more potently by a first series of synthetic activators based on a pyrrolo[1,2-a]quinoxaline scaffold.^[17] Crystal structures of Sirt6/activator complexes show that the compounds exploit a SIRT6 specific pocket in the enzyme's substrate acyl binding channel.^[17] Among many anthocyanidins studied, cyanidin most potently stimulated activity of the SIRT6.^[12]