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NAD-dependent protein deacylase sirtuin-6

Definition:

NAD-dependent protein deacetylase, deacylase and mono-ADP-ribosyltransferase that plays an essential role in DNA damage repair, telomere maintenance, metabolic homeostasis, inflammation, tumorigenesis and aging. Displays protein-lysine deacetylase or defatty-acylase (demyristoylase and depalmitoylase) activity, depending on the context. Acts as a key histone deacetylase by catalyzing deacetylation of histone H3 at 'Lys-9', 'Lys-18' and 'Lys-56' (H3K9ac, H3K18ac and H3K56ac, respectively), suppressing target gene expression of several transcription factors, including NF-kappa-B. Acts as an inhibitor of transcription elongation by mediating deacetylation of H3K9ac and H3K56ac, preventing release of NELFE from chromatin and causing transcriptional pausing (By similarity). Involved in DNA repair by promoting double-strand break (DSB) repair: acts as a DSB sensor by recognizing and binding DSB sites, leading to (1) recruitment of DNA repair proteins, such as SMARCA5/SNF2H, and (2) deacetylation of histone H3K9ac and H3K56ac. SIRT6 participation to DSB repair is probably involved in extension of life span (By similarity). Also promotes DNA repair by deacetylating non-histone proteins, such as DDB2 and p53/TP53. Specifically deacetylates H3K18ac at pericentric heterochromatin, thereby maintaining pericentric heterochromatin silencing at centromeres and protecting against genomic instability and cellular senescence. Involved in telomere maintenance by catalyzing deacetylation of histone H3 in telomeric chromatin, regulating telomere position effect and telomere movement in response to DNA damage. Required for embryonic stem cell differentiation by mediating histone deacetylation of H3K9ac. Plays a major role in metabolism by regulating processes such as glycolysis, gluconeogenesis, insulin secretion and lipid metabolism. Inhibits glycolysis via histone deacetylase activity and by acting as a corepressor of the transcription factor HIF1A, thereby controlling the expression of multiple glycolytic genes (By similarity). Has tumor suppressor activity by repressing glycolysis, thereby inhibiting the Warburg effect. Also regulates glycolysis and tumorigenesis by mediating deacetylation and nuclear export of non-histone proteins, such as isoform M2 of PKM (PKM2). Acts as a negative regulator of gluconeogenesis by mediating deacetylation of non-histone proteins, such as FOXO1 and KAT2A/GCN5. Promotes beta-oxidation of fatty acids during fasting by catalyzing deacetylation of NCOA2, inducing coactivation of PPARA (By similarity). Acts as a regulator of lipid catabolism in brown adipocytes, both by catalyzing deacetylation of histones and non-histone proteins, such as FOXO1 (By similarity). Also acts as a regulator of circadian rhythms, both by regulating expression of clock-controlled genes involved in lipid and carbohydrate metabolism, and by catalyzing deacetylation of PER2 (By similarity). The defatty-acylase activity is specifically involved in regulation of protein secretion. 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. Also acts as a mono-ADP-ribosyltransferase by mediating mono-ADP-ribosylation of PARP1, TRIM28/KAP1 or SMARCC2/BAF170. Mono-ADP-ribosyltransferase activity is involved in DNA repair, cellular senescence, repression of LINE-1 retrotransposon elements and regulation of transcription.

References:

[1]. Lior Onn, et al. SIRT6 is a DNA double-strand break sensor. Elife. 2020 Jan 29;9:e51636. [Content Brief]

[2]. Sivan Elhanati, et al. Multiple regulatory layers of SREBP1/2 by SIRT6. Cell Rep. 2013 Sep 12;4(5):905-12. [Content Brief]

[3]. Patricia W Pan, et al. Structure and biochemical functions of SIRT6. J Biol Chem. 2011 Apr 22;286(16):14575-87. [Content Brief]

[4]. Sita Kugel, et al. SIRT6 Suppresses Pancreatic Cancer through Control of Lin28b. Cell. 2016 Jun 2;165(6):1401-1415. [Content Brief]

[5]. Zhiyong Mao, et al. SIRT6 promotes DNA repair under stress by activating PARP1. Science. 2011 Jun 17;332(6036):1443-6. [Content Brief]

[6]. Reuven Gil, et al. SIRT6 exhibits nucleosome-dependent deacetylase activity. Nucleic Acids Res. 2013 Oct;41(18):8537-45. [Content Brief]

[7]. Xiaoyu Zhang, et al. SIRT6 regulates Ras-related protein R-Ras2 by lysine defatty-acylation. Elife. 2017 Apr 13;6:e25158. [Content Brief]

[8]. Zhimin Huang, et al. Identification of a cellularly active SIRT6 allosteric activator. Nat Chem Biol. 2018 Dec;14(12):1118-1126. [Content Brief]

[9]. Ruth I Tennen, et al. SIRT6 is required for maintenance of telomere position effect in human cells. Nat Commun. 2011 Aug 16;2:433. [Content Brief]

[10]. Shrestha Ghosh, et al. Haploinsufficiency of Trp53 dramatically extends the lifespan of Sirt6-deficient mice. Elife. 2018 Feb 23;7:e32127. [Content Brief]

[11]. Hong Jiang, et al. SIRT6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine. Nature. 2013 Apr 4;496(7443):110-3. [Content Brief]

[12]. Eriko Michishita, et al. SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature. 2008 Mar 27;452(7186):492-6. [Content Brief]

[13]. Xiaoyu Zhang, et al. Identifying the functional contribution of the defatty-acylase activity of SIRT6. Nat Chem Biol. 2016 Aug;12(8):614-20. [Content Brief]

[14]. Carlos Sebastián, et al. The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell. 2012 Dec 7;151(6):1185-99. [Content Brief]

[15]. Sita Kugel, et al. Identification of and Molecular Basis for SIRT6 Loss-of-Function Point Mutations in Cancer. Cell Rep. 2015 Oct 20;13(3):479-488. [Content Brief]

[16]. Eriko Michishita, et al. Cell cycle-dependent deacetylation of telomeric histone H3 lysine K56 by human SIRT6. Cell Cycle. 2009 Aug 15;8(16):2664-6. [Content Brief]

[17]. Anke Geng, et al. The deacetylase SIRT6 promotes the repair of UV-induced DNA damage by targeting DDB2. Nucleic Acids Res. 2020 Sep 18;48(16):9181-9194. [Content Brief]

[18]. Wallace H Liu, et al. Multivalent interactions drive nucleosome binding and efficient chromatin deacetylation by SIRT6. Nat Commun. 2020 Oct 16;11(1):5244. [Content Brief]

[19]. Amit Sharma, et al. The role of SIRT6 protein in aging and reprogramming of human induced pluripotent stem cells. J Biol Chem. 2013 Jun 21;288(25):18439-47. [Content Brief]

[20]. Christina M Ferrer, et al. An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality. Genes Dev. 2018 Mar 1;32(5-6):373-388. [Content Brief]

[21]. Debra Toiber, et al. SIRT6 recruits SNF2H to DNA break sites, preventing genomic instability through chromatin remodeling. Mol Cell. 2013 Aug 22;51(4):454-68. [Content Brief]

[22]. John E Dominy Jr, et al. The deacetylase Sirt6 activates the acetyltransferase GCN5 and suppresses hepatic gluconeogenesis. Mol Cell. 2012 Dec 28;48(6):900-13. [Content Brief]

[23]. Abhishek Bhardwaj, et al. SIRT6 deacetylates PKM2 to suppress its nuclear localization and oncogenic functions. Proc Natl Acad Sci U S A. 2016 Feb 2;113(5):E538-47. [Content Brief]

[24]. Tiara L A Kawahara, et al. SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span. Cell. 2009 Jan 9;136(1):62-74. [Content Brief]

[25]. Luisa Tasselli, et al. SIRT6 deacetylates H3K18ac at pericentric chromatin to prevent mitotic errors and cellular senescence. Nat Struct Mol Biol. 2016 May;23(5):434-40. [Content Brief]

[26]. J Cai, et al. A crucial role of SUMOylation in modulating Sirt6 deacetylation of H3 at lysine 56 and its tumor suppressive activity. Oncogene. 2016 Sep 15;35(37):4949-56. [Content Brief]

[27]. Zhiyong Mao, et al. Sirtuin 6 (SIRT6) rescues the decline of homologous recombination repair during replicative senescence. Proc Natl Acad Sci U S A. 2012 Jul 17;109(29):11800-5. [Content Brief]

[28]. Fanbiao Meng, et al. Synergy between SIRT1 and SIRT6 helps recognize DNA breaks and potentiates the DNA damage response and repair in humans and mice. Elife. 2020 Jun 15;9:e55828. [Content Brief]

[29]. Ping Zhang, et al. Tumor suppressor p53 cooperates with SIRT6 to regulate gluconeogenesis by promoting FoxO1 nuclear exclusion. Proc Natl Acad Sci U S A. 2014 Jul 22;111(29):10684-9. [Content Brief]

[30]. Jessica L Feldman, et al. Activation of the protein deacetylase SIRT6 by long-chain fatty acids and widespread deacylation by mammalian sirtuins. J Biol Chem. 2013 Oct 25;288(43):31350-6. [Content Brief]

[31]. Jean-Pierre Etchegaray, et al. The histone deacetylase SIRT6 controls embryonic stem cell fate via TET-mediated production of 5-hydroxymethylcytosine. Nat Cell Biol. 2015 May;17(5):545-57. [Content Brief]

[32]. Michael Van Meter, et al. JNK Phosphorylates SIRT6 to Stimulate DNA Double-Strand Break Repair in Response to Oxidative Stress by Recruiting PARP1 to DNA Breaks. Cell Rep. 2016 Sep 6;16(10):2641-2650. [Content Brief]

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