Selected-GenAtlas references SOURCE GeneCards NCBI Gene Swiss-Prot Ensembl
HGNC UniGene Nucleotide OMIM UCSC
Home Page
Symbol SIRT6 contributors: mct/pgu/shn - updated : 21-01-2015
HGNC name sirtuin 6
HGNC id 14934
Location 19p13.3      Physical location : 4.174.106 - 4.182.596
Synonym name
  • sirtuin (silent mating type information regulation 2 homolog) 6 (S. cerevisiae)
  • mono-ADP-ribosyltransferase sirtuin-6
  • SIR2-like protein 6
  • sirtuin type 6
  • sir2-related protein type 6
  • NAD-dependent deacetylase sirtuin-6
  • Synonym symbol(s) SIR2L6
    TYPE functioning gene
    STRUCTURE 8.49 kb     8 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status confirmed
    Map pter - D19S424 - D19S209 - SIRT6 - D19S894 - D19S216 - cen
    regionally located between CDC34 and D19S325
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    8 splicing 1657 39 355 - 2008 18337721
    7 splicing 1555 - 328 - 2008 18337721
    Type widely
       expressed in (based on citations)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveintestinesmall intestine  moderately
     intestinelarge intestinecolon moderately
    Lymphoid/Immunespleen   highly
    Nervousbrain   highly Homo sapiens
    Reproductivefemale systemovary  predominantly
    Skin/Tegumentskin   moderately
    Visualeye   moderately
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectivebone  highly
    Nervouscentral  highly Homo sapiens
    cell lineage
    cell lines
    fluid/secretion highly in blood
    at STAGE
  • a deacetylase sirtuin-type core domain
  • a putative catalytic sirtuin core with N- and C-terminal flanking extensions
  • a 10-AAs insertion between the second set of cysteines, resulting in an extended long loop
  • a zinc-binding motif in the small domain
  • secondary structure
  • two globular domains composed of eight alpha-helices and nine beta-strands
  • helix bundle is replaced by a short loop, which interacts with the loop between alpha2 and alpha3 and contacts a small region on the zinc-binding module
  • conjugated RiboP
    mono polymer complex
    interspecies ortholog to sirt6, Danio rerio
    homolog to Sir2 deacetylase, Yeast
    ortholog to Sirt6, Rattus norvegicus
    ortholog to Sirt6, Mus musculus
    ortholog to SIRT6, Pan troglodytes
  • class IV of the sirtuin family
  • CATEGORY enzyme , regulatory , tumor suppressor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,endoplasmic reticulum
  • chromatin silencing complex
  • mainly localized in the nucleus, but might be present in secretory organelles, such as the endoplasmic reticulum
  • basic FUNCTION
  • being a NAD(+) ADP ribosyltransferase with a protein deacetylase activity
  • a nuclear, chromatin-associated protein that promotes resistance to DNA damage and suppresses genomic instability in association with a role in base excision repair (
  • by participating in the stress response to genomic insults, sirtuins are thought to protect against cancer, but they are also emerging as direct participants in the growth of some cancers
  • an NAD+-dependent, histone H3 lysine 9 (H3K9) deacetylase that modulates telomeric chromatin (
  • plays critical roles in intermediary metabolism and genomic stability
  • NAD-dependent deacetylases promoting longevity
  • functions at chromatin to attenuate NF-KB signaling, via H3K9 deacetylation at chromatin
  • inhibits expression of a subset of NF-KB target genes, especially those associated with aging
  • modulates apoptosis resistance and telomere-independent cellular senescence in human cells, via inhibition of NF-KB
  • important for DNA repair, transcriptional regulation of genes important for metabolism and immune responses, and for lifespan
  • forms a macromolecular complex with the DNA double-strand break (DSB) repair factor PRKDC (DNA-dependent protein kinase) and promotes DNA DSB repair
  • function as a corepressor of the transcription factor HIF1A, a critical regulator of nutrient stress responses
  • functions as a histone H3K9 deacetylase to control the expression of multiple glycolytic genes (
  • functions as a corepressor of the transcription factor Hif1alpha, a critical regulator of nutrient stress responses (
  • a master regulator of glucose homeostasis (
  • plays a critical role in fat metabolism
  • has a role in promoting DNA end resection, a crucial step in DNA double-strand break (DSB) repair by homologous recombination
  • essential role of SIRT6 in modulating glucose metabolism through mediating insulin sensitivity
  • functions as a central regulator of somatic growth and plays an important role in preventing obesity by modulating neural chromatin structure and gene activity
  • major H3K9 and H3K56 deacetylase in the brain, suggesting potential roles in regulation of gene activity
  • neural SIRT6 as a regulator of the somatic growth axis and a potential disease factor for adult-onset obesity
  • having a poor deacetylase activity (a less stable substrate-protein interaction might be the cause of this poor deacetylase activity)
  • displays tight binding of NAD+ in the absence of an acetylated substrate
  • could be able to bind NAD+ in the absence of an acetylated substrate
  • might ensure metabolic homeostasis and promote more efficient energy usage through its ability to sense the levels of NAD+ (and related metabolites) and regulate protein-protein interactions with transcription factors
  • recruited to the sites of DNA double-strand breaks (DSBs) and stimulates DSB repair under oxidative stress (
  • activation provides a potential therapeutic strategy to prevent the decline in genome maintenance
  • is a tumor suppressor that regulates aerobic glycolysis in cancer cells
  • SIRT6 expression is downregulated in human cancers, strongly reinforcing the idea that SIRT6 is a novel tumor suppressor
  • is likely a tumor suppressor involved in both cancer initiation and tumor growth
  • represses tumorigenesis by inhibiting a glycolytic switch required for cancer cell proliferation
  • promotes the secretion of tumour necrosis factor-alpha(TNF) by removing the fatty acyl modification on K19 and K20 of TNF
  • important role of hepatic SIRT6 and FOXO3 in the regulation of cholesterol homeostasis
  • preferentially hydrolyze long-chain fatty acyl groups over acetyl groups
  • CELLULAR PROCESS nucleotide, repair
    nucleotide, genomic integrity
  • protein ADP-ribosylation, chromatin silencing
  • NAD+-dependent ADP-ribosyl transferase activity
    a component
  • chromatin silencing complex
  • ADP-ribosylated
  • telomeres (
  • RNA
    small molecule metal binding, cofactor, nucleotide,
  • Zn2+ (one zinc ion per subunit)
  • can bind NAD+ with a relatively high affinity in the absence of an acetylated substrate
  • protein
  • grap2 cyclin interacting protein, GCIP (
  • binds to the NFKB3 subunit RELA and attenuates NF-KB signaling by modifying chromatin at NF-KB target genes (might associate with promoters of RELA target genes)
  • recruited to chromatin at the promoters of RELA target genes, via its physical interaction with RELA
  • DNA-dependent protein kinase, DNA-PK (
  • deacetylates RBBP8 to promote resection and homologous recombination
  • negatively control the mRNA expression of glycolytic and lipogenic genes
  • poly[adenosine diphosphate (ADP)-ribose] polymerase 1 (PARP1) and mono-ADP-ribosylates PARP1 (
  • inhibits ribosomal gene expression by co-repressing MYC transcriptional activity
  • SIRT6 is a critical factor for SREBF2 gene regulation
  • FOXO3 and SIRT6, two longevity genes, can reduce LDL-cholesterol levels through regulation of the PCSK9 gene
  • KAT8 participates in human hepatocellular carcinoma by targeting SIRT6
  • SIRT6, a sirtuin with established tumor suppressor function, regulates the lysine fatty acylation of RRAS2
  • cell & other
    induced by TP53
    Other protein stabilization increased upon nutrient deprivation
    corresponding disease(s)
    Variant & Polymorphism
    Candidate gene
    Therapy target
    may serve as a therapeutic target for treating fatty liver disease, the most common cause of liver dysfunction in humans
    novel therapeutic approaches against metabolic diseases, such as diabetes and obesity
  • mice deficient for SIRT6 are small and at 2-3 weeks of age develop abnormalities that include profound lymphopenia, loss of subcutaneous fat, lordokyphosis, and severe metabolic defects, eventually dying at about 4 weeks and exhibit genome instability (
  • SIRT6-deficient mice develop normally but succumb to a lethal hypoglycemia early in life (
  • SIRT6-deficient cells exhibit increased Hif1alpha activity and show increased glucose uptake with upregulation of glycolysis and diminished mitochondrial respiration (
  • Abrogation of these SIRT6 activities leads to impaired resolution of DNA double-strand break (
  • liver-specific deletion of SIRT6 in mice causes profound alterations in gene expression, leading to increased glycolysis, triglyceride synthesis, reduced beta oxidation, and fatty liver formation
  • mice overexpressing Sirt6 are protected against diet-induced obesity
  • SIRT6(-/-) animals had very low levels of blood glucose and died shortly after weaning
  • SIRT6-deficient mice have a striking degenerative phenotype leading to shortened lifespan and are associated with hypoglycemia and defects in DNA repair