Protein-coding gene in the species Homo sapiens
SIRT6 |
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![](//upload.wikimedia.org/wikipedia/commons/thumb/8/88/Human_Sirt6_protein.jpg/250px-Human_Sirt6_protein.jpg) |
Available structures |
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PDB | Ortholog search: PDBe RCSB |
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List of PDB id codes |
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3K35, 3PKI, 3PKJ, 3ZG6 |
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Identifiers |
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Aliases | SIRT6, SIR2L6, sirtuin 6 |
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External IDs | OMIM: 606211; MGI: 1354161; HomoloGene: 6924; GeneCards: SIRT6; OMA:SIRT6 - orthologs |
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Gene location (Human) |
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![Chromosome 19 (human)](//upload.wikimedia.org/wikipedia/commons/thumb/5/54/Ideogram_human_chromosome_19.svg/300px-Ideogram_human_chromosome_19.svg.png) | Chr. | Chromosome 19 (human)[1] |
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| Band | 19p13.3 | Start | 4,174,109 bp[1] |
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End | 4,182,566 bp[1] |
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Gene location (Mouse) |
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![Chromosome 10 (mouse)](//upload.wikimedia.org/wikipedia/commons/thumb/4/4e/Ideogram_house_mouse_chromosome_10.svg/260px-Ideogram_house_mouse_chromosome_10.svg.png) | Chr. | Chromosome 10 (mouse)[2] |
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| Band | 10 C1|10 39.72 cM | Start | 81,457,619 bp[2] |
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End | 81,463,631 bp[2] |
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RNA expression pattern |
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Bgee | Human | Mouse (ortholog) |
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Top expressed in | - mucosa of transverse colon
- granulocyte
- tendon of biceps brachii
- anterior pituitary
- right hemisphere of cerebellum
- body of pancreas
- apex of heart
- spleen
- left adrenal cortex
- right adrenal gland
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| Top expressed in | - morula
- neural tube
- zygote
- ventricular zone
- yolk sac
- blastocyst
- granulocyte
- lip
- ascending aorta
- embryo
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| More reference expression data |
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BioGPS | ![](//upload.wikimedia.org/wikipedia/commons/thumb/e/ed/PBB_GE_SIRT6_219613_s_at_fs.png/250px-PBB_GE_SIRT6_219613_s_at_fs.png) | More reference expression data |
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Gene ontology |
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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 |
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Orthologs |
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Species | Human | Mouse |
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Entrez | | |
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Ensembl | | |
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UniProt | | |
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RefSeq (mRNA) | NM_001193285 NM_016539 NM_001321058 NM_001321059 NM_001321060
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NM_001321061 NM_001321062 NM_001321063 NM_001321064 |
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NM_001163430 NM_181586 NM_001378944 NM_001378945 |
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RefSeq (protein) | NP_001180214 NP_001307987 NP_001307988 NP_001307989 NP_001307990
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NP_001307991 NP_001307992 NP_001307993 NP_057623 |
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NP_001156902 NP_853617 NP_001365873 NP_001365874 |
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Location (UCSC) | Chr 19: 4.17 – 4.18 Mb | Chr 10: 81.46 – 81.46 Mb |
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PubMed search | [3] | [4] |
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Wikidata |
View/Edit Human | View/Edit Mouse |
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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.
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+).[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]
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.[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]
Activators
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]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000077463 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000034748 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b Frye RA (July 2000). "Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins". Biochemical and Biophysical Research Communications. 273 (2): 793–98. doi:10.1006/bbrc.2000.3000. PMID 10873683.
- ^ "Entrez Gene: SIRT6 sirtuin (silent mating type information regulation 2 homolog) 6 (S. cerevisiae)".
- ^ Van Meter M, Mao Z, Gorbunova V, Seluanov A (2011). "Repairing split ends: SIRT6, mono-ADP ribosylation and DNA repair". Aging. 3 (9): 829–835. doi:10.18632/aging.100389. PMC 3227448. PMID 21946623.
- ^ Bonkowski MS, Sinclair DA (2016). "Slowing ageing by design: the rise of NAD + and sirtuin-activating compounds". Nat Rev Mol Cell Biol. 17 (11): 679–690. doi:10.1038/nrm.2016.93. PMC 5107309. PMID 27552971.
- ^ Kanfi Y, Naiman S, Amir G, Peshti V, Zinman G, Nahum L, Bar-Joseph Z, Cohen HY (February 2012). "The sirtuin SIRT6 regulates lifespan in male mice". Nature. 483 (7388): 218–21. Bibcode:2012Natur.483..218K. doi:10.1038/nature10815. PMID 22367546. S2CID 4417564.
- ^ a b Mostoslavsky R, Chua KF, Lombard DB, Pang WW, Fischer MR, Gellon L, Liu P, Mostoslavsky G, Franco S, Murphy MM, Mills KD, Patel P, Hsu JT, Hong AL, Ford E, Cheng HL, Kennedy C, Nunez N, Bronson R, Frendewey D, Auerbach W, Valenzuela D, Karow M, Hottiger MO, Hursting S, Barrett JC, Guarente L, Mulligan R, Demple B, Yancopoulos GD, Alt FW (January 2006). "Genomic instability and aging-like phenotype in the absence of mammalian SIRT6". Cell. 124 (2): 315–29. doi:10.1016/j.cell.2005.11.044. PMID 16439206. S2CID 18517518.
- ^ a b Tian X, Firsanov D, Seluanov A, Vera Gorbunova V (2019). "SIRT6 Is Responsible for More Efficient DNA Double-Strand Break Repair in Long-Lived Species". Cell. 177 (3): 622–638. doi:10.1016/j.cell.2019.03.043. PMC 6499390. PMID 31002797.
- ^ a b Klein MA, Denu JM (2020). "Biological and catalytic functions of sirtuin 6 as targets for small-molecule modulators". Journal of Biological Chemistry. 295 (32): 11021–11041. doi:10.1074/jbc.REV120.011438. PMC 7415977. PMID 32518153.
- ^ McCord RA, Michishita E, Hong T, Berber E, Boxer LD, Kusumoto R, Guan S, Shi X, Gozani O, Burlingame AL, Bohr VA, Chua KF (January 2009). "SIRT6 stabilizes DNA-dependent protein kinase at chromatin for DNA double-strand break repair". Aging. 1 (1): 109–21. doi:10.18632/aging.100011. PMC 2815768. PMID 20157594.
- ^ a b Mao Z, Tian X, Van Meter M, Ke Z, Gorbunova V, Seluanov A (July 2012). "Sirtuin 6 (SIRT6) rescues the decline of homologous recombination repair during replicative senescence". Proceedings of the National Academy of Sciences of the United States of America. 109 (29): 11800–05. Bibcode:2012PNAS..10911800M. doi:10.1073/pnas.1200583109. PMC 3406824. PMID 22753495.
- ^ Xu Z, Zhang L, Zhang W, Meng D, Zhang H, Jiang Y, Xu X, Van Meter M, Seluanov A, Gorbunova V, Mao Z (2015). "SIRT6 rescues the age related decline in base excision repair in a PARP1-dependent manner". Cell Cycle. 14 (2): 269–76. doi:10.4161/15384101.2014.980641. PMC 4614943. PMID 25607651.
- ^ Feldman JL, Baeza J, Denu JM (October 2013). "Activation of the protein deacetylase SIRT6 by long-chain fatty acids and widespread deacylation by mammalian sirtuins". The Journal of Biological Chemistry. 288 (43): 31350–56. doi:10.1074/jbc.C113.511261. PMC 3829447. PMID 24052263.
- ^ a b You W, Rotili D, Li TM, Kambach C, Meleshin M, Schutkowski M, Chua KF, Mai A, Steegborn C (January 2017). "Structural Basis of Sirtuin 6 Activation by Synthetic Small Molecules". Angewandte Chemie. 56 (4): 1007–11. doi:10.1002/anie.201610082. PMID 27990725.
External links
- FactorBook SIRT6
- Overview of all the structural information available in the PDB for UniProt: Q8N6T7 (NAD-dependent protein deacetylase sirtuin-6) at the PDBe-KB.