SIRT6
Description
The SIRT6 (sirtuin 6) is a protein-coding gene located on chromosome 19.
Sirtuin 6 (SIRT6 or Sirt6) is a stress responsive protein deacetylase and mono-ADP ribosyltransferase enzyme encoded by the SIRT6 gene. In laboratory research, SIRT6 appears to function in multiple molecular pathways related to aging, including DNA repair, telomere maintenance, glycolysis and inflammation. SIRT6 is member of the mammalian sirtuin family of proteins, which are homologs to the yeast Sir2 protein.
== Research == 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+). 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.
== DNA repair == 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. Deficiency of SIRT6 in mice leads to abnormalities that overlap with aging-associated degenerative processes. A study of 18 species of rodents showed that the longevity of the species was correlated with the efficiency of the SIRT6 enzyme.
SIRT6 is a NAD-dependent protein deacetylase, deacylase and mono-ADP-ribosyltransferase that plays a critical role in various cellular processes, including DNA damage repair, telomere maintenance, metabolic homeostasis, inflammation, tumorigenesis and aging. It can act as a protein-lysine deacetylase or defatty-acylase (demyristoylase and depalmitoylase) depending on the context. As a key histone deacetylase, it catalyzes deacetylation of histone H3 at 'Lys-9', 'Lys-18' and 'Lys-56', suppressing target gene expression of several transcription factors, including NF-kappa-B. SIRT6 also functions as an inhibitor of transcription elongation by deacetylating H3K9ac and H3K56ac, preventing the release of NELFE from chromatin and causing transcriptional pausing. SIRT6 is involved in DNA repair by promoting double-strand break (DSB) repair. It acts as a DSB sensor by recognizing and binding to DSB sites, leading to recruitment of DNA repair proteins, such as SMARCA5/SNF2H, and deacetylation of histone H3K9ac and H3K56ac. SIRT6 also promotes DNA repair by deacetylating non-histone proteins, such as DDB2 and p53/TP53. It specifically deacetylates H3K18ac at pericentric heterochromatin, maintaining pericentric heterochromatin silencing at centromeres and protecting against genomic instability and cellular senescence. SIRT6 is involved in telomere maintenance by deacetylating histone H3 in telomeric chromatin, regulating telomere position effect and telomere movement in response to DNA damage. It is required for embryonic stem cell differentiation by mediating histone deacetylation of H3K9ac. SIRT6 plays a major role in metabolism by regulating processes such as glycolysis, gluconeogenesis, insulin secretion and lipid metabolism. It inhibits glycolysis via histone deacetylase activity and by acting as a corepressor of the transcription factor HIF1A, controlling the expression of multiple glycolytic genes. SIRT6 has tumor suppressor activity by repressing glycolysis, inhibiting the Warburg effect. It also regulates glycolysis and tumorigenesis by mediating deacetylation and nuclear export of non-histone proteins, such as isoform M2 of PKM (PKM2). SIRT6 acts as a negative regulator of gluconeogenesis by deacetylating non-histone proteins, such as FOXO1 and KAT2A/GCN5. It promotes beta-oxidation of fatty acids during fasting by deacetylating NCOA2, inducing coactivation of PPARA. SIRT6 acts as a regulator of lipid catabolism in brown adipocytes by deacetylating both histones and non-histone proteins, such as FOXO1. It also functions as a regulator of circadian rhythms by regulating expression of clock-controlled genes involved in lipid and carbohydrate metabolism, and by deacetylating PER2. The defatty-acylase activity of SIRT6 is specifically involved in regulation of protein secretion. It 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. SIRT6 also acts as a mono-ADP-ribosyltransferase by mediating mono-ADP-ribosylation of PARP1, TRIM28/KAP1 or SMARCC2/BAF170. This activity is involved in DNA repair, cellular senescence, repression of LINE-1 retrotransposon elements and regulation of transcription. SIRT6 exists as a homodimer, binding to nucleosomes and DNA ends. It interacts with RELA, interfering with RELA binding to target DNA. It also interacts with SMARCA5, promoting recruitment of SMARCA5/SNF2H to double-strand breaks (DSBs) sites. SIRT6 interacts with the mTORC2 complex, preventing its ability to deacetylate FOXO1. It also interacts with the CLOCK-BMAL1 complex, being recruited by it to regulate expression of clock-controlled genes. SIRT6 interacts with CSNK2A2, preventing its localization to the nucleus. In the context of microbial infection, SIRT6 interacts with Kaposi's sarcoma-associated herpesvirus protein VIRF-1, preventing its deubiquitination by USP10.
SIRT6 is also known as SIR2L6, hSIRT6.
