Sirtuin 6

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.

SIRT6
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesSIRT6, SIR2L6, sirtuin 6
External IDsOMIM: 606211 MGI: 1354161 HomoloGene: 6924 GeneCards: SIRT6
Orthologs
SpeciesHumanMouse
Entrez

51548

50721

Ensembl

ENSG00000077463

ENSMUSG00000034748

UniProt

Q8N6T7

P59941

RefSeq (mRNA)

NM_001163430
NM_181586
NM_001378944
NM_001378945

RefSeq (protein)

NP_001156902
NP_853617
NP_001365873
NP_001365874

Location (UCSC)Chr 19: 4.17 – 4.18 MbChr 10: 81.46 – 81.46 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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
  1. GRCh38: Ensembl release 89: ENSG00000077463 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000034748 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 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.
  6. "Entrez Gene: SIRT6 sirtuin (silent mating type information regulation 2 homolog) 6 (S. cerevisiae)".
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
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