SIR6_MOUSE
ID SIR6_MOUSE Reviewed; 334 AA.
AC P59941;
DT 31-OCT-2003, integrated into UniProtKB/Swiss-Prot.
DT 31-OCT-2003, sequence version 1.
DT 03-AUG-2022, entry version 141.
DE RecName: Full=NAD-dependent protein deacylase sirtuin-6 {ECO:0000305};
DE EC=2.3.1.- {ECO:0000250|UniProtKB:Q8N6T7};
DE AltName: Full=NAD-dependent protein deacetylase sirtuin-6 {ECO:0000305};
DE EC=2.3.1.286 {ECO:0000255|PROSITE-ProRule:PRU00236, ECO:0000269|PubMed:15795229, ECO:0000269|PubMed:29555651, ECO:0000269|PubMed:29599436, ECO:0000269|PubMed:31002797, ECO:0000269|PubMed:31399344};
DE AltName: Full=Protein mono-ADP-ribosyltransferase sirtuin-6 {ECO:0000305};
DE EC=2.4.2.- {ECO:0000269|PubMed:25247314, ECO:0000269|PubMed:31216030, ECO:0000305|PubMed:32584788};
DE AltName: Full=Regulatory protein SIR2 homolog 6 {ECO:0000303|PubMed:15795229};
DE Short=mSIRT6 {ECO:0000303|PubMed:15795229};
DE AltName: Full=SIR2-like protein 6;
GN Name=Sirt6 {ECO:0000303|PubMed:15795229, ECO:0000312|MGI:MGI:1354161};
GN Synonyms=Sir2l6;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Limb;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [2]
RP CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, DEVELOPMENTAL
RP STAGE, ACTIVE SITE, AND MUTAGENESIS OF SER-56 AND HIS-133.
RX PubMed=15795229; DOI=10.1074/jbc.m413296200;
RA Liszt G., Ford E., Kurtev M., Guarente L.;
RT "Mouse Sir2 homolog SIRT6 is a nuclear ADP-ribosyltransferase.";
RL J. Biol. Chem. 280:21313-21320(2005).
RN [3]
RP DISRUPTION PHENOTYPE, FUNCTION, SUBCELLULAR LOCATION, AND TISSUE
RP SPECIFICITY.
RX PubMed=16439206; DOI=10.1016/j.cell.2005.11.044;
RA Mostoslavsky R., Chua K.F., Lombard D.B., Pang W.W., Fischer M.R.,
RA Gellon L., Liu P., Mostoslavsky G., Franco S., Murphy M.M., Mills K.D.,
RA Patel P., Hsu J.T., Hong A.L., Ford E., Cheng H.-L., Kennedy C., Nunez N.,
RA Bronson R., Frendewey D., Auerbach W., Valenzuela D., Karow M.,
RA Hottiger M.O., Hursting S., Barrett J.C., Guarente L., Mulligan R.,
RA Demple B., Yancopoulos G.D., Alt F.W.;
RT "Genomic instability and aging-like phenotype in the absence of mammalian
RT SIRT6.";
RL Cell 124:315-329(2006).
RN [4]
RP FUNCTION.
RX PubMed=19220062; DOI=10.1021/bi802093g;
RA Du J., Jiang H., Lin H.;
RT "Investigating the ADP-ribosyltransferase activity of sirtuins with NAD
RT analogues and 32P-NAD.";
RL Biochemistry 48:2878-2890(2009).
RN [5]
RP FUNCTION, AND INTERACTION WITH RELA.
RX PubMed=19135889; DOI=10.1016/j.cell.2008.10.052;
RA Kawahara T.L.A., Michishita E., Adler A.S., Damian M., Berber E., Lin M.,
RA McCord R.A., Ongaigui K.C.L., Boxer L.D., Chang H.Y., Chua K.F.;
RT "SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene
RT expression and organismal life span.";
RL Cell 136:62-74(2009).
RN [6]
RP FUNCTION, ACTIVE SITE, AND MUTAGENESIS OF HIS-133.
RX PubMed=19597350; DOI=10.4161/cc.8.16.9329;
RA Yang B., Zwaans B.M.M., Eckersdorff M., Lombard D.B.;
RT "The sirtuin SIRT6 deacetylates H3 K56Ac in vivo to promote genomic
RT stability.";
RL Cell Cycle 8:2662-2663(2009).
RN [7]
RP FUNCTION.
RX PubMed=19151729; DOI=10.1038/nm.1906;
RA Van Gool F., Galli M., Gueydan C., Kruys V., Prevot P.P., Bedalov A.,
RA Mostoslavsky R., Alt F.W., De Smedt T., Leo O.;
RT "Intracellular NAD levels regulate tumor necrosis factor protein synthesis
RT in a sirtuin-dependent manner.";
RL Nat. Med. 15:206-210(2009).
RN [8]
RP FUNCTION IN REGULATION OF GLUCOSE HOMEOSTASIS.
RX PubMed=20141841; DOI=10.1016/j.cell.2009.12.041;
RA Zhong L., D'Urso A., Toiber D., Sebastian C., Henry R.E.,
RA Vadysirisack D.D., Guimaraes A., Marinelli B., Wikstrom J.D., Nir T.,
RA Clish C.B., Vaitheesvaran B., Iliopoulos O., Kurland I., Dor Y.,
RA Weissleder R., Shirihai O.S., Ellisen L.W., Espinosa J.M., Mostoslavsky R.;
RT "The histone deacetylase Sirt6 regulates glucose homeostasis via
RT Hif1alpha.";
RL Cell 140:280-293(2010).
RN [9]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=20816089; DOI=10.1016/j.cmet.2010.06.009;
RA Kim H.S., Xiao C., Wang R.H., Lahusen T., Xu X., Vassilopoulos A.,
RA Vazquez-Ortiz G., Jeong W.I., Park O., Ki S.H., Gao B., Deng C.X.;
RT "Hepatic-specific disruption of SIRT6 in mice results in fatty liver
RT formation due to enhanced glycolysis and triglyceride synthesis.";
RL Cell Metab. 12:224-236(2010).
RN [10]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=20847051; DOI=10.1074/jbc.m110.168039;
RA Xiao C., Kim H.S., Lahusen T., Wang R.H., Xu X., Gavrilova O., Jou W.,
RA Gius D., Deng C.X.;
RT "SIRT6 deficiency results in severe hypoglycemia by enhancing both basal
RT and insulin-stimulated glucose uptake in mice.";
RL J. Biol. Chem. 285:36776-36784(2010).
RN [11]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=21098266; DOI=10.1073/pnas.1016306107;
RA Schwer B., Schumacher B., Lombard D.B., Xiao C., Kurtev M.V., Gao J.,
RA Schneider J.I., Chai H., Bronson R.T., Tsai L.H., Deng C.X., Alt F.W.;
RT "Neural sirtuin 6 (Sirt6) ablation attenuates somatic growth and causes
RT obesity.";
RL Proc. Natl. Acad. Sci. U.S.A. 107:21790-21794(2010).
RN [12]
RP FUNCTION.
RX PubMed=21680843; DOI=10.1126/science.1202723;
RA Mao Z., Hine C., Tian X., Van Meter M., Au M., Vaidya A., Seluanov A.,
RA Gorbunova V.;
RT "SIRT6 promotes DNA repair under stress by activating PARP1.";
RL Science 332:1443-1446(2011).
RN [13]
RP FUNCTION.
RX PubMed=23217706; DOI=10.1016/j.cell.2012.10.047;
RA Sebastian C., Zwaans B.M., Silberman D.M., Gymrek M., Goren A., Zhong L.,
RA Ram O., Truelove J., Guimaraes A.R., Toiber D., Cosentino C.,
RA Greenson J.K., MacDonald A.I., McGlynn L., Maxwell F., Edwards J.,
RA Giacosa S., Guccione E., Weissleder R., Bernstein B.E., Regev A.,
RA Shiels P.G., Lombard D.B., Mostoslavsky R.;
RT "The histone deacetylase SIRT6 is a tumor suppressor that controls cancer
RT metabolism.";
RL Cell 151:1185-1199(2012).
RN [14]
RP FUNCTION IN REGULATION OF LIFE SPAN.
RX PubMed=22367546; DOI=10.1038/nature10815;
RA Kanfi Y., Naiman S., Amir G., Peshti V., Zinman G., Nahum L.,
RA Bar-Joseph Z., Cohen H.Y.;
RT "The sirtuin SIRT6 regulates lifespan in male mice.";
RL Nature 483:218-221(2012).
RN [15]
RP FUNCTION.
RX PubMed=23142079; DOI=10.1016/j.molcel.2012.09.030;
RA Dominy J.E. Jr., Lee Y., Jedrychowski M.P., Chim H., Jurczak M.J.,
RA Camporez J.P., Ruan H.B., Feldman J., Pierce K., Mostoslavsky R.,
RA Denu J.M., Clish C.B., Yang X., Shulman G.I., Gygi S.P., Puigserver P.;
RT "The deacetylase Sirt6 activates the acetyltransferase GCN5 and suppresses
RT hepatic gluconeogenesis.";
RL Mol. Cell 48:900-913(2012).
RN [16]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=23974119; DOI=10.1074/jbc.m113.481473;
RA Tao R., Xiong X., DePinho R.A., Deng C.X., Dong X.C.;
RT "FoxO3 transcription factor and Sirt6 deacetylase regulate low density
RT lipoprotein (LDL)-cholesterol homeostasis via control of the proprotein
RT convertase subtilisin/kexin type 9 (Pcsk9) gene expression.";
RL J. Biol. Chem. 288:29252-29259(2013).
RN [17]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=23911928; DOI=10.1016/j.molcel.2013.06.018;
RA Toiber D., Erdel F., Bouazoune K., Silberman D.M., Zhong L., Mulligan P.,
RA Sebastian C., Cosentino C., Martinez-Pastor B., Giacosa S., D'Urso A.,
RA Naeaer A.M., Kingston R., Rippe K., Mostoslavsky R.;
RT "SIRT6 recruits SNF2H to DNA break sites, preventing genomic instability
RT through chromatin remodeling.";
RL Mol. Cell 51:454-468(2013).
RN [18]
RP SUBCELLULAR LOCATION.
RX PubMed=23552949; DOI=10.1038/nature12038;
RA Jiang H., Khan S., Wang Y., Charron G., He B., Sebastian C., Du J., Kim R.,
RA Ge E., Mostoslavsky R., Hang H.C., Hao Q., Lin H.;
RT "SIRT6 regulates TNF-alpha secretion through hydrolysis of long-chain fatty
RT acyl lysine.";
RL Nature 496:110-113(2013).
RN [19]
RP FUNCTION, AND INTERACTION WITH THE CLOCK-BMAL1 COMPLEX.
RX PubMed=25083875; DOI=10.1016/j.cell.2014.06.050;
RA Masri S., Rigor P., Cervantes M., Ceglia N., Sebastian C., Xiao C.,
RA Roqueta-Rivera M., Deng C., Osborne T.F., Mostoslavsky R., Baldi P.,
RA Sassone-Corsi P.;
RT "Partitioning circadian transcription by SIRT6 leads to segregated control
RT of cellular metabolism.";
RL Cell 158:659-672(2014).
RN [20]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF SER-56; GLY-60 AND ARG-65.
RX PubMed=25247314; DOI=10.1038/ncomms6011;
RA Van Meter M., Kashyap M., Rezazadeh S., Geneva A.J., Morello T.D.,
RA Seluanov A., Gorbunova V.;
RT "SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this
RT repression fails with stress and age.";
RL Nat. Commun. 5:5011-5011(2014).
RN [21]
RP FUNCTION.
RX PubMed=25009184; DOI=10.1073/pnas.1411026111;
RA Zhang P., Tu B., Wang H., Cao Z., Tang M., Zhang C., Gu B., Li Z., Wang L.,
RA Yang Y., Zhao Y., Wang H., Luo J., Deng C.X., Gao B., Roeder R.G.,
RA Zhu W.G.;
RT "Tumor suppressor p53 cooperates with SIRT6 to regulate gluconeogenesis by
RT promoting FoxO1 nuclear exclusion.";
RL Proc. Natl. Acad. Sci. U.S.A. 111:10684-10689(2014).
RN [22]
RP FUNCTION.
RX PubMed=25915124; DOI=10.1038/ncb3147;
RA Etchegaray J.P., Chavez L., Huang Y., Ross K.N., Choi J.,
RA Martinez-Pastor B., Walsh R.M., Sommer C.A., Lienhard M., Gladden A.,
RA Kugel S., Silberman D.M., Ramaswamy S., Mostoslavsky G., Hochedlinger K.,
RA Goren A., Rao A., Mostoslavsky R.;
RT "The histone deacetylase SIRT6 controls embryonic stem cell fate via TET-
RT mediated production of 5-hydroxymethylcytosine.";
RL Nat. Cell Biol. 17:545-557(2015).
RN [23]
RP FUNCTION.
RX PubMed=27180906; DOI=10.1016/j.cell.2016.04.033;
RA Kugel S., Sebastian C., Fitamant J., Ross K.N., Saha S.K., Jain E.,
RA Gladden A., Arora K.S., Kato Y., Rivera M.N., Ramaswamy S., Sadreyev R.I.,
RA Goren A., Deshpande V., Bardeesy N., Mostoslavsky R.;
RT "SIRT6 suppresses pancreatic cancer through control of Lin28b.";
RL Cell 165:1401-1415(2016).
RN [24]
RP FUNCTION.
RX PubMed=27322069; DOI=10.1038/nchembio.2106;
RA Zhang X., Khan S., Jiang H., Antonyak M.A., Chen X., Spiegelman N.A.,
RA Shrimp J.H., Cerione R.A., Lin H.;
RT "Identifying the functional contribution of the defatty-acylase activity of
RT SIRT6.";
RL Nat. Chem. Biol. 12:614-620(2016).
RN [25]
RP FUNCTION, DISRUPTION PHENOTYPE, AND MUTAGENESIS OF TYR-133.
RX PubMed=27457971; DOI=10.1038/srep30321;
RA Song M.Y., Wang J., Ka S.O., Bae E.J., Park B.H.;
RT "Insulin secretion impairment in Sirt6 knockout pancreatic beta cells is
RT mediated by suppression of the FoxO1-Pdx1-Glut2 pathway.";
RL Sci. Rep. 6:30321-30321(2016).
RN [26]
RP FUNCTION, AND INTERACTION WITH CSNK2A2.
RX PubMed=28355567; DOI=10.1016/j.celrep.2017.03.006;
RA Chen Q., Hao W., Xiao C., Wang R., Xu X., Lu H., Chen W., Deng C.X.;
RT "SIRT6 is essential for adipocyte differentiation by regulating mitotic
RT clonal expansion.";
RL Cell Rep. 18:3155-3166(2017).
RN [27]
RP FUNCTION, INDUCTION BY COLD, AND DISRUPTION PHENOTYPE.
RX PubMed=28723567; DOI=10.1016/j.celrep.2017.06.069;
RA Yao L., Cui X., Chen Q., Yang X., Fang F., Zhang J., Liu G., Jin W.,
RA Chang Y.;
RT "Cold-inducible SIRT6 regulates thermogenesis of brown and beige fat.";
RL Cell Rep. 20:641-654(2017).
RN [28]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=28250020; DOI=10.2337/db16-1225;
RA Kuang J., Zhang Y., Liu Q., Shen J., Pu S., Cheng S., Chen L., Li H.,
RA Wu T., Li R., Li Y., Zou M., Zhang Z., Jiang W., Xu G., Qu A., Xie W.,
RA He J.;
RT "Fat-Specific Sirt6 Ablation Sensitizes Mice to High-Fat Diet-Induced
RT Obesity and Insulin Resistance by Inhibiting Lipolysis.";
RL Diabetes 66:1159-1171(2017).
RN [29]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=28871079; DOI=10.1038/s41467-017-00498-4;
RA Liu M., Liang K., Zhen J., Zhou M., Wang X., Wang Z., Wei X., Zhang Y.,
RA Sun Y., Zhou Z., Su H., Zhang C., Li N., Gao C., Peng J., Yi F.;
RT "Sirt6 deficiency exacerbates podocyte injury and proteinuria through
RT targeting Notch signaling.";
RL Nat. Commun. 8:413-413(2017).
RN [30]
RP DISRUPTION PHENOTYPE.
RX PubMed=28448551; DOI=10.1371/journal.pone.0176371;
RA Peshti V., Obolensky A., Nahum L., Kanfi Y., Rathaus M., Avraham M.,
RA Tinman S., Alt F.W., Banin E., Cohen H.Y.;
RT "Characterization of physiological defects in adult SIRT6-/- mice.";
RL PLoS ONE 12:e0176371-e0176371(2017).
RN [31]
RP DISRUPTION PHENOTYPE.
RX PubMed=29474172; DOI=10.7554/elife.32127;
RA Ghosh S., Wong S.K., Jiang Z., Liu B., Wang Y., Hao Q., Gorbunova V.,
RA Liu X., Zhou Z.;
RT "Haploinsufficiency of Trp53 dramatically extends the lifespan of Sirt6-
RT deficient mice.";
RL Elife 7:0-0(2018).
RN [32]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF ASP-63.
RX PubMed=29555651; DOI=10.1101/gad.307330.117;
RA Ferrer C.M., Alders M., Postma A.V., Park S., Klein M.A., Cetinbas M.,
RA Pajkrt E., Glas A., van Koningsbruggen S., Christoffels V.M.,
RA Mannens M.M.A.M., Knegt L., Etchegaray J.P., Sadreyev R.I., Denu J.M.,
RA Mostoslavsky G., van Maarle M.C., Mostoslavsky R.;
RT "An inactivating mutation in the histone deacetylase SIRT6 causes human
RT perinatal lethality.";
RL Genes Dev. 32:373-388(2018).
RN [33]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF HIS-133.
RX PubMed=29599436; DOI=10.1038/s41598-018-23602-0;
RA Gao Y., Tan J., Jin J., Ma H., Chen X., Leger B., Xu J., Spagnol S.T.,
RA Dahl K.N., Levine A.S., Liu Y., Lan L.;
RT "SIRT6 facilitates directional telomere movement upon oxidative damage.";
RL Sci. Rep. 8:5407-5407(2018).
RN [34]
RP FUNCTION.
RX PubMed=30782483; DOI=10.1016/j.bbrc.2019.01.143;
RA Sun S., Liu Z., Feng Y., Shi L., Cao X., Cai Y., Liu B.;
RT "Sirt6 deacetylase activity regulates circadian rhythms via Per2.";
RL Biochem. Biophys. Res. Commun. 511:234-238(2019).
RN [35]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF ARG-235; GLN-249 AND
RP 260-GLU--ARG-264.
RX PubMed=31002797; DOI=10.1016/j.cell.2019.03.043;
RA Tian X., Firsanov D., Zhang Z., Cheng Y., Luo L., Tombline G., Tan R.,
RA Simon M., Henderson S., Steffan J., Goldfarb A., Tam J., Zheng K.,
RA Cornwell A., Johnson A., Yang J.N., Mao Z., Manta B., Dang W., Zhang Z.,
RA Vijg J., Wolfe A., Moody K., Kennedy B.K., Bohmann D., Gladyshev V.N.,
RA Seluanov A., Gorbunova V.;
RT "SIRT6 is responsible for more efficient DNA double-strand break repair in
RT long-lived species.";
RL Cell 177:622-638(2019).
RN [36]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=30853213; DOI=10.1016/j.cmet.2019.02.014;
RA Simon M., Van Meter M., Ablaeva J., Ke Z., Gonzalez R.S., Taguchi T.,
RA De Cecco M., Leonova K.I., Kogan V., Helfand S.L., Neretti N., Roichman A.,
RA Cohen H.Y., Meer M.V., Gladyshev V.N., Antoch M.P., Gudkov A.V.,
RA Sedivy J.M., Seluanov A., Gorbunova V.;
RT "LINE1 derepression in aged wild-type and SIRT6-deficient mice drives
RT inflammation.";
RL Cell Metab. 29:871-885(2019).
RN [37]
RP FUNCTION.
RX PubMed=31851938; DOI=10.1016/j.celrep.2019.11.067;
RA Naiman S., Huynh F.K., Gil R., Glick Y., Shahar Y., Touitou N., Nahum L.,
RA Avivi M.Y., Roichman A., Kanfi Y., Gertler A.A., Doniger T., Ilkayeva O.R.,
RA Abramovich I., Yaron O., Lerrer B., Gottlieb E., Harris R.A., Gerber D.,
RA Hirschey M.D., Cohen H.Y.;
RT "SIRT6 promotes hepatic beta-oxidation via activation of PPARalpha.";
RL Cell Rep. 29:4127-4143(2019).
RN [38]
RP FUNCTION, INDUCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=30530497; DOI=10.1074/jbc.ra118.005309;
RA Chen L., Liu Q., Tang Q., Kuang J., Li H., Pu S., Wu T., Yang X., Li R.,
RA Zhang J., Zhang Z., Huang Y., Li Y., Zou M., Jiang W., Li T., Gong M.,
RA Zhang L., Wang H., Qu A., Xie W., He J.;
RT "Hepatocyte-specific Sirt6 deficiency impairs ketogenesis.";
RL J. Biol. Chem. 294:1579-1589(2019).
RN [39]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=31399344; DOI=10.1016/j.molcel.2019.06.034;
RA Etchegaray J.P., Zhong L., Li C., Henriques T., Ablondi E., Nakadai T.,
RA Van Rechem C., Ferrer C., Ross K.N., Choi J.E., Samarakkody A., Ji F.,
RA Chang A., Sadreyev R.I., Ramaswamy S., Nechaev S., Whetstine J.R.,
RA Roeder R.G., Adelman K., Goren A., Mostoslavsky R.;
RT "The histone deacetylase SIRT6 restrains transcription elongation via
RT promoter-proximal pausing.";
RL Mol. Cell 75:683-699(2019).
RN [40]
RP FUNCTION, AND INTERACTION WITH MTORC2.
RX PubMed=31442424; DOI=10.1016/j.molcel.2019.07.023;
RA Jung S.M., Hung C.M., Hildebrand S.R., Sanchez-Gurmaches J.,
RA Martinez-Pastor B., Gengatharan J.M., Wallace M., Mukhopadhyay D.,
RA Martinez Calejman C., Luciano A.K., Hsiao W.Y., Tang Y., Li H.,
RA Daniels D.L., Mostoslavsky R., Metallo C.M., Guertin D.A.;
RT "Non-canonical mTORC2 signaling regulates brown adipocyte lipid catabolism
RT through SIRT6-FoxO1.";
RL Mol. Cell 75:807-822(2019).
RN [41]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF GLY-60;
RP ARG-65 AND HIS-133.
RX PubMed=31216030; DOI=10.1093/nar/gkz528;
RA Rezazadeh S., Yang D., Tombline G., Simon M., Regan S.P., Seluanov A.,
RA Gorbunova V.;
RT "SIRT6 promotes transcription of a subset of NRF2 targets by mono-ADP-
RT ribosylating BAF170.";
RL Nucleic Acids Res. 47:7914-7928(2019).
RN [42]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=32584788; DOI=10.18632/aging.103567;
RA Rezazadeh S., Yang D., Biashad S.A., Firsanov D., Takasugi M., Gilbert M.,
RA Tombline G., Bhanu N.V., Garcia B.A., Seluanov A., Gorbunova V.;
RT "SIRT6 mono-ADP ribosylates KDM2A to locally increase H3K36me2 at DNA
RT damage sites to inhibit transcription and promote repair.";
RL Aging (Albany NY) 12:11165-11184(2020).
RN [43]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=32538779; DOI=10.7554/elife.55828;
RA Meng F., Qian M., Peng B., Peng L., Wang X., Zheng K., Liu Z., Tang X.,
RA Zhang S., Sun S., Cao X., Pang Q., Zhao B., Ma W., Songyang Z., Xu B.,
RA Zhu W.G., Xu X., Liu B.;
RT "Synergy between SIRT1 and SIRT6 helps recognize DNA breaks and potentiates
RT the DNA damage response and repair in humans and mice.";
RL Elife 9:0-0(2020).
RN [44]
RP FUNCTION.
RX PubMed=34050173; DOI=10.1038/s41467-021-23545-7;
RA Roichman A., Elhanati S., Aon M.A., Abramovich I., Di Francesco A.,
RA Shahar Y., Avivi M.Y., Shurgi M., Rubinstein A., Wiesner Y., Shuchami A.,
RA Petrover Z., Lebenthal-Loinger I., Yaron O., Lyashkov A., Ubaida-Mohien C.,
RA Kanfi Y., Lerrer B., Fernandez-Marcos P.J., Serrano M., Gottlieb E.,
RA de Cabo R., Cohen H.Y.;
RT "Restoration of energy homeostasis by SIRT6 extends healthy lifespan.";
RL Nat. Commun. 12:3208-3208(2021).
CC -!- FUNCTION: NAD-dependent protein deacetylase, deacylase and mono-ADP-
CC ribosyltransferase that plays an essential role in DNA damage repair,
CC telomere maintenance, metabolic homeostasis, inflammation,
CC tumorigenesis and aging (PubMed:16439206, PubMed:19135889,
CC PubMed:20141841, PubMed:19220062, PubMed:19597350, PubMed:23217706,
CC PubMed:23911928, PubMed:27180906, PubMed:29599436). Displays protein-
CC lysine deacetylase or defatty-acylase (demyristoylase and
CC depalmitoylase) activity, depending on the context (By similarity).
CC Acts as a key histone deacetylase by catalyzing deacetylation of
CC histone H3 at 'Lys-9', 'Lys-18' and 'Lys-56' (H3K9ac, H3K18ac and
CC H3K56ac, respectively), suppressing target gene expression of several
CC transcription factors, including NF-kappa-B (PubMed:19135889,
CC PubMed:19597350, PubMed:20816089, PubMed:21098266, PubMed:25915124,
CC PubMed:28871079, PubMed:31002797, PubMed:31399344). Acts as an
CC inhibitor of transcription elongation by mediating deacetylation of
CC H3K9ac and H3K56ac, preventing release of NELFE from chromatin and
CC causing transcriptional pausing (PubMed:31399344). Involved in DNA
CC repair by promoting double-strand break (DSB) repair: acts as a DSB
CC sensor by recognizing and binding DSB sites, leading to (1) recruitment
CC of DNA repair proteins, such as SMARCA5/SNF2H, and (2) deacetylation of
CC histone H3K9ac and H3K56ac (PubMed:32538779). SIRT6 participation to
CC DSB repair is probably involved in extension of life span
CC (PubMed:22367546, PubMed:31002797). Also promotes DNA repair by
CC deacetylating non-histone proteins, such as DDB2 and p53/TP53 (By
CC similarity). Specifically deacetylates H3K18ac at pericentric
CC heterochromatin, thereby maintaining pericentric heterochromatin
CC silencing at centromeres and protecting against genomic instability and
CC cellular senescence (By similarity). Involved in telomere maintenance
CC by catalyzing deacetylation of histone H3 in telomeric chromatin,
CC regulating telomere position effect and telomere movement in response
CC to DNA damage (PubMed:29599436). Required for embryonic stem cell
CC differentiation by mediating histone deacetylation of H3K9ac
CC (PubMed:25915124, PubMed:29555651). Plays a major role in metabolism by
CC regulating processes such as glycolysis, gluconeogenesis, insulin
CC secretion and lipid metabolism (PubMed:20141841, PubMed:20816089,
CC PubMed:20847051, PubMed:21098266, PubMed:23974119, PubMed:27457971,
CC PubMed:28355567, PubMed:28250020, PubMed:34050173). Inhibits glycolysis
CC via histone deacetylase activity and by acting as a corepressor of the
CC transcription factor HIF1A, thereby controlling the expression of
CC multiple glycolytic genes (PubMed:20141841). Has tumor suppressor
CC activity by repressing glycolysis, thereby inhibiting the Warburg
CC effect (PubMed:23217706). Also regulates glycolysis and tumorigenesis
CC by mediating deacetylation and nuclear export of non-histone proteins,
CC such as isoform M2 of PKM (PKM2) (By similarity). Acts as a negative
CC regulator of gluconeogenesis by mediating deacetylation of non-histone
CC proteins, such as FOXO1 and KAT2A/GCN5 (PubMed:23142079,
CC PubMed:25009184). Promotes beta-oxidation of fatty acids during fasting
CC by catalyzing deacetylation of NCOA2, inducing coactivation of PPARA
CC (PubMed:31851938). Acts as a regulator of lipid catabolism in brown
CC adipocytes, both by catalyzing deacetylation of histones and non-
CC histone proteins, such as FOXO1 (PubMed:28723567, PubMed:31442424).
CC Also acts as a regulator of circadian rhythms, both by regulating
CC expression of clock-controlled genes involved in lipid and carbohydrate
CC metabolism, and by catalyzing deacetylation of PER2 (PubMed:25083875,
CC PubMed:30782483). The defatty-acylase activity is specifically involved
CC in regulation of protein secretion (PubMed:19151729, PubMed:27322069).
CC Has high activity toward long-chain fatty acyl groups and mediates
CC protein-lysine demyristoylation and depalmitoylation of target
CC proteins, such as RRAS2 and TNF, thereby regulating their secretion (By
CC similarity). Also acts as a mono-ADP-ribosyltransferase by mediating
CC mono-ADP-ribosylation of PARP1, TRIM28/KAP1 or SMARCC2/BAF170
CC (PubMed:15795229, PubMed:21680843, PubMed:25247314, PubMed:31216030).
CC Mono-ADP-ribosyltransferase activity is involved in DNA repair,
CC cellular senescence, repression of LINE-1 retrotransposon elements and
CC regulation of transcription (PubMed:21680843, PubMed:25247314,
CC PubMed:30853213, PubMed:31216030, PubMed:32584788).
CC {ECO:0000250|UniProtKB:Q8N6T7, ECO:0000269|PubMed:15795229,
CC ECO:0000269|PubMed:16439206, ECO:0000269|PubMed:19135889,
CC ECO:0000269|PubMed:19151729, ECO:0000269|PubMed:19220062,
CC ECO:0000269|PubMed:19597350, ECO:0000269|PubMed:20141841,
CC ECO:0000269|PubMed:20816089, ECO:0000269|PubMed:20847051,
CC ECO:0000269|PubMed:21098266, ECO:0000269|PubMed:21680843,
CC ECO:0000269|PubMed:22367546, ECO:0000269|PubMed:23142079,
CC ECO:0000269|PubMed:23217706, ECO:0000269|PubMed:23911928,
CC ECO:0000269|PubMed:23974119, ECO:0000269|PubMed:25009184,
CC ECO:0000269|PubMed:25083875, ECO:0000269|PubMed:25247314,
CC ECO:0000269|PubMed:25915124, ECO:0000269|PubMed:27180906,
CC ECO:0000269|PubMed:27322069, ECO:0000269|PubMed:27457971,
CC ECO:0000269|PubMed:28250020, ECO:0000269|PubMed:28355567,
CC ECO:0000269|PubMed:28723567, ECO:0000269|PubMed:28871079,
CC ECO:0000269|PubMed:29555651, ECO:0000269|PubMed:29599436,
CC ECO:0000269|PubMed:30782483, ECO:0000269|PubMed:30853213,
CC ECO:0000269|PubMed:31002797, ECO:0000269|PubMed:31216030,
CC ECO:0000269|PubMed:31399344, ECO:0000269|PubMed:31442424,
CC ECO:0000269|PubMed:31851938, ECO:0000269|PubMed:32538779,
CC ECO:0000269|PubMed:32584788, ECO:0000269|PubMed:34050173}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N(6)-acetyl-L-lysyl-[protein] + NAD(+) = 2''-O-acetyl-
CC ADP-D-ribose + L-lysyl-[protein] + nicotinamide;
CC Xref=Rhea:RHEA:43636, Rhea:RHEA-COMP:9752, Rhea:RHEA-COMP:10731,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:17154, ChEBI:CHEBI:29969,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:61930, ChEBI:CHEBI:83767;
CC EC=2.3.1.286; Evidence={ECO:0000255|PROSITE-ProRule:PRU00236,
CC ECO:0000269|PubMed:15795229, ECO:0000269|PubMed:29555651,
CC ECO:0000269|PubMed:29599436, ECO:0000269|PubMed:31002797,
CC ECO:0000269|PubMed:31399344};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:43637;
CC Evidence={ECO:0000269|PubMed:15795229, ECO:0000269|PubMed:29555651,
CC ECO:0000269|PubMed:29599436, ECO:0000269|PubMed:31002797,
CC ECO:0000269|PubMed:31399344};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N(6)-tetradecanoyl-L-lysyl-[protein] + NAD(+) = 2''-O-
CC tetradecanoyl-ADP-D-ribose + L-lysyl-[protein] + nicotinamide;
CC Xref=Rhea:RHEA:70567, Rhea:RHEA-COMP:9752, Rhea:RHEA-COMP:15437,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:17154, ChEBI:CHEBI:29969,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:141129, ChEBI:CHEBI:189674;
CC Evidence={ECO:0000250|UniProtKB:Q8N6T7};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70568;
CC Evidence={ECO:0000250|UniProtKB:Q8N6T7};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N(6)-hexadecanoyl-L-lysyl-[protein] + NAD(+) = 2''-O-
CC hexadecanoyl-ADP-D-ribose + L-lysyl-[protein] + nicotinamide;
CC Xref=Rhea:RHEA:70563, Rhea:RHEA-COMP:9752, Rhea:RHEA-COMP:14175,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:17154, ChEBI:CHEBI:29969,
CC ChEBI:CHEBI:57540, ChEBI:CHEBI:138936, ChEBI:CHEBI:189673;
CC Evidence={ECO:0000250|UniProtKB:Q8N6T7};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70564;
CC Evidence={ECO:0000250|UniProtKB:Q8N6T7};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-lysyl-[protein] + NAD(+) = H(+) + N(6)-(ADP-D-ribosyl)-L-
CC lysyl-[protein] + nicotinamide; Xref=Rhea:RHEA:58220, Rhea:RHEA-
CC COMP:9752, Rhea:RHEA-COMP:15088, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:17154, ChEBI:CHEBI:29969, ChEBI:CHEBI:57540,
CC ChEBI:CHEBI:142515; Evidence={ECO:0000269|PubMed:25247314,
CC ECO:0000269|PubMed:31216030};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:58221;
CC Evidence={ECO:0000269|PubMed:25247314, ECO:0000269|PubMed:31216030};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-arginyl-[protein] + NAD(+) = H(+) + N(omega)-(ADP-D-
CC ribosyl)-L-arginyl-[protein] + nicotinamide; Xref=Rhea:RHEA:19149,
CC Rhea:RHEA-COMP:10532, Rhea:RHEA-COMP:15087, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:17154, ChEBI:CHEBI:29965, ChEBI:CHEBI:57540,
CC ChEBI:CHEBI:142554; Evidence={ECO:0000305|PubMed:32584788};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19150;
CC Evidence={ECO:0000305|PubMed:32584788};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000250|UniProtKB:Q8N6T7};
CC Note=Binds 1 zinc ion per subunit. {ECO:0000250|UniProtKB:Q8N6T7};
CC -!- ACTIVITY REGULATION: Compared to the defatty-acylase activity, the
CC protein deacetylase activity is weak in vitro, and requires activation
CC (By similarity). The histone deacetylase activity is strongly activated
CC upon binding to nucleosomes and chromatin in vivo (By similarity). Two
CC molecules of SIRT6 associate with the acidic patch of one nucleosome,
CC while the C-terminal disordered region of SIRT6 associates with
CC nucleosomal DNA, leading to efficient histone deacetylation (By
CC similarity). The protein-lysine deacetylase activity is also activated
CC by long-chain free fatty-acids (By similarity).
CC {ECO:0000250|UniProtKB:Q8N6T7}.
CC -!- SUBUNIT: Homodimer; binds to nucleosomes and DNA ends as a homodimer
CC (By similarity). Interacts with RELA; interferes with RELA binding to
CC target DNA (PubMed:19135889). Interacts with SMARCA5; promoting
CC recruitment of SMARCA5/SNF2H to double-strand breaks (DSBs) sites (By
CC similarity). Interacts with the mTORC2 complex; preventing the ability
CC of SIRT6 to deacetylate FOXO1 (PubMed:31442424). Interacts with the
CC CLOCK-BMAL1 complex; recruited by the CLOCK-BMAL1 complex to regulate
CC expression of clock-controlled genes (PubMed:25083875). Interacts with
CC CSNK2A2; preventing CSNK2A2 localization to the nucleus
CC (PubMed:28355567). {ECO:0000250|UniProtKB:Q8N6T7,
CC ECO:0000269|PubMed:19135889, ECO:0000269|PubMed:25083875,
CC ECO:0000269|PubMed:28355567, ECO:0000269|PubMed:31442424}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:15795229,
CC ECO:0000269|PubMed:16439206}. Chromosome
CC {ECO:0000250|UniProtKB:Q8N6T7}. Chromosome, telomere
CC {ECO:0000250|UniProtKB:Q8N6T7}. Endoplasmic reticulum
CC {ECO:0000269|PubMed:23552949}. Note=Predominantly nuclear (By
CC similarity). Associated with pericentric heterochromatin and telomeric
CC heterochromatin regions (By similarity). Localizes to DNA damage sites:
CC directly recognizes and binds double-strand breaks (DSBs) sites via a
CC tunnel-like structure that has high affinity for DSBs (By similarity).
CC A fraction localizes to the endoplasmic reticulum (PubMed:23552949).
CC {ECO:0000250|UniProtKB:Q8N6T7, ECO:0000269|PubMed:23552949}.
CC -!- TISSUE SPECIFICITY: Highest levels are found in muscle, thymus, spleen,
CC brain and heart (at protein level). {ECO:0000269|PubMed:15795229,
CC ECO:0000269|PubMed:16439206}.
CC -!- DEVELOPMENTAL STAGE: Expression peaks at embryonic day 11 and persists
CC into adulthood. {ECO:0000269|PubMed:15795229}.
CC -!- INDUCTION: By cold (PubMed:28723567). In hepatocytes, expression is
CC increased following incubation in a ketonic medium (PubMed:30530497).
CC {ECO:0000269|PubMed:28723567, ECO:0000269|PubMed:30530497}.
CC -!- DOMAIN: The C-terminal disordered region mediates non-specific DNA-
CC binding. {ECO:0000250|UniProtKB:Q8N6T7}.
CC -!- PTM: Acetylated at Lys-33 (By similarity). Deacetylation at Lys-33 by
CC SIRT1 promotes homomultimerization and binding to double-strand breaks
CC (DSBs) sites (By similarity). {ECO:0000250|UniProtKB:Q8N6T7}.
CC -!- PTM: Phosphorylation at Ser-10 by MAPK8/JNK1 in response to oxidative
CC stress stimulates the mono-ADP-ribosyltransferase activity on PARP1,
CC leading to PARP1 recruitment to double-strand breaks (DSBs).
CC {ECO:0000250|UniProtKB:Q8N6T7}.
CC -!- PTM: Monoubiquitinated at Lys-170 by STUB1/CHIP, preventing its
CC degradation by the proteasome. {ECO:0000250|UniProtKB:Q8N6T7}.
CC -!- PTM: Sumoylated, leading to specifically decrease ability to
CC deacetylate histone H3 at 'Lys-56' (H3K56ac).
CC {ECO:0000250|UniProtKB:Q8N6T7}.
CC -!- DISRUPTION PHENOTYPE: Mice display multiple defects, accelerated aging
CC and die a few weeks after birth, because of impaired genomic stability
CC (PubMed:16439206). Mice do not show any visible phenotype at birth and
CC undergo a normal development during the first two weeks, except for
CC reduced growth (PubMed:16439206). By two/three weeks of age, mice in a
CC 129/SvJ background display severe metabolic defects and develop
CC abnormalities usually associated with aging (PubMed:16439206,
CC PubMed:20847051). These include acute loss of subcutaneous fat,
CC lordokyphosis, erosion of the superficial colon epithelium, severe
CC lymphopenia, osteopenia and severely reduced IGF1 serum levels
CC (PubMed:16439206). Severe hypoglycemia, characterized by very low
CC levels of blood glucose, is also observed (PubMed:16439206,
CC PubMed:20847051). Mice also show defects in DNA double-strand break
CC (DSB) repair (PubMed:23911928, PubMed:32538779). Derepression of LINE-1
CC retrotransposon elements is also observed, leading to an accumulation
CC of cytoplasmic L1 cDNAs, which triggers the cGAS-STING pathway, driving
CC inflammation (PubMed:30853213). Mice die about 24 days after birth
CC (PubMed:16439206). Mice in a mixed 129/SvJ and BALB/c background reach
CC adulthood: at 200 days of age, more than 80% of the female mice survive
CC whereas only 10% of male mice are alive (PubMed:28448551). Mutant mice
CC in this mixed background (129/SvJ and BALB/c) display reduced body
CC weight, increased glucose uptake and exhibit an age-dependent
CC progressive impairment of retinal function accompanied by thinning of
CC retinal layers (PubMed:28448551). Sirt6-deficient mice that are
CC haploinsufficient with p53/Tp53 display a strongly extended life span
CC in both females and males (PubMed:29474172). Conditional deletion in
CC the liver leads to increased glycolysis, fatty liver, triglyceride
CC synthesis and reduced beta-oxidation (PubMed:20816089). Conditional
CC deletion in the liver also leads to elevated LDL-cholesterol levels
CC (PubMed:23974119). Conditional deletion in hepatocytes leads to
CC impaired ketogenesis (PubMed:30530497). Conditional deletion in
CC adipocytes promotes high-fat diet-induced obesity because of impaired
CC lipolytic activity (PubMed:28723567, PubMed:28250020). Conditional
CC deletion in pancretic beta-cells leads to glucose intolerance with
CC severely impaired glucose-stimulated insulin secretion
CC (PubMed:27457971). Conditional deletion in neurons leads to postnatal
CC growth retardation and obesity (PubMed:21098266). Conditional deletion
CC in podocytes exacerbates podocyte injury and proteinuria; defects are
CC caused by derepression of the Notch signaling (PubMed:28871079).
CC {ECO:0000269|PubMed:16439206, ECO:0000269|PubMed:20816089,
CC ECO:0000269|PubMed:20847051, ECO:0000269|PubMed:21098266,
CC ECO:0000269|PubMed:23911928, ECO:0000269|PubMed:23974119,
CC ECO:0000269|PubMed:27457971, ECO:0000269|PubMed:28250020,
CC ECO:0000269|PubMed:28448551, ECO:0000269|PubMed:28723567,
CC ECO:0000269|PubMed:28871079, ECO:0000269|PubMed:29474172,
CC ECO:0000269|PubMed:30530497, ECO:0000269|PubMed:30853213,
CC ECO:0000269|PubMed:32538779}.
CC -!- MISCELLANEOUS: Compared to beaver, mouse SIRT6 displays lower histone
CC deacetylase activity and ability to promote double-strand break (DSB)
CC repair, possibly leading to shorter life span.
CC {ECO:0000269|PubMed:31002797}.
CC -!- SIMILARITY: Belongs to the sirtuin family. Class IV subfamily.
CC {ECO:0000305}.
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DR EMBL; BC052763; AAH52763.1; -; mRNA.
DR CCDS; CCDS24066.1; -.
DR RefSeq; NP_853617.1; NM_181586.3.
DR AlphaFoldDB; P59941; -.
DR SMR; P59941; -.
DR BioGRID; 206064; 3.
DR IntAct; P59941; 1.
DR STRING; 10090.ENSMUSP00000048971; -.
DR iPTMnet; P59941; -.
DR PhosphoSitePlus; P59941; -.
DR EPD; P59941; -.
DR jPOST; P59941; -.
DR MaxQB; P59941; -.
DR PaxDb; P59941; -.
DR PRIDE; P59941; -.
DR ProteomicsDB; 261372; -.
DR Antibodypedia; 11389; 711 antibodies from 42 providers.
DR DNASU; 50721; -.
DR Ensembl; ENSMUST00000042923; ENSMUSP00000048971; ENSMUSG00000034748.
DR GeneID; 50721; -.
DR KEGG; mmu:50721; -.
DR UCSC; uc007giy.2; mouse.
DR CTD; 51548; -.
DR MGI; MGI:1354161; Sirt6.
DR VEuPathDB; HostDB:ENSMUSG00000034748; -.
DR eggNOG; KOG1905; Eukaryota.
DR GeneTree; ENSGT00940000160088; -.
DR HOGENOM; CLU_023643_6_0_1; -.
DR InParanoid; P59941; -.
DR OMA; EQCKKCR; -.
DR OrthoDB; 1503290at2759; -.
DR PhylomeDB; P59941; -.
DR TreeFam; TF106184; -.
DR BRENDA; 2.3.1.B41; 3474.
DR Reactome; R-MMU-5693607; Processing of DNA double-strand break ends.
DR BioGRID-ORCS; 50721; 12 hits in 113 CRISPR screens.
DR ChiTaRS; Sirt6; mouse.
DR PRO; PR:P59941; -.
DR Proteomes; UP000000589; Chromosome 10.
DR RNAct; P59941; protein.
DR Bgee; ENSMUSG00000034748; Expressed in embryonic brain and 113 other tissues.
DR ExpressionAtlas; P59941; baseline and differential.
DR Genevisible; P59941; MM.
DR GO; GO:0000785; C:chromatin; ISS:UniProtKB.
DR GO; GO:0099115; C:chromosome, subtelomeric region; ISS:GO_Central.
DR GO; GO:0005737; C:cytoplasm; ISO:MGI.
DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0005721; C:pericentric heterochromatin; ISO:MGI.
DR GO; GO:0090734; C:site of DNA damage; ISO:MGI.
DR GO; GO:0035861; C:site of double-strand break; ISO:MGI.
DR GO; GO:0003682; F:chromatin binding; IDA:MGI.
DR GO; GO:0031490; F:chromatin DNA binding; ISS:UniProtKB.
DR GO; GO:0003684; F:damaged DNA binding; ISS:UniProtKB.
DR GO; GO:0019213; F:deacetylase activity; IBA:GO_Central.
DR GO; GO:0140612; F:DNA damage sensor activity; ISS:UniProtKB.
DR GO; GO:0004407; F:histone deacetylase activity; IBA:GO_Central.
DR GO; GO:0106222; F:lncRNA binding; ISO:MGI.
DR GO; GO:0070403; F:NAD+ binding; ISS:UniProtKB.
DR GO; GO:1990404; F:NAD+-protein ADP-ribosyltransferase activity; IDA:UniProtKB.
DR GO; GO:0106274; F:NAD+-protein-arginine ADP-ribosyltransferase activity; IDA:UniProtKB.
DR GO; GO:0017136; F:NAD-dependent histone deacetylase activity; ISS:UniProtKB.
DR GO; GO:0097372; F:NAD-dependent histone deacetylase activity (H3-K18 specific); IDA:UniProtKB.
DR GO; GO:0140765; F:NAD-dependent histone deacetylase activity (H3-K56 specific); IDA:UniProtKB.
DR GO; GO:0046969; F:NAD-dependent histone deacetylase activity (H3-K9 specific); IDA:UniProtKB.
DR GO; GO:0034979; F:NAD-dependent protein deacetylase activity; IDA:UniProtKB.
DR GO; GO:0140773; F:NAD-dependent protein demyristoylase activity; ISS:UniProtKB.
DR GO; GO:0140774; F:NAD-dependent protein depalmitoylase activity; ISS:UniProtKB.
DR GO; GO:0031491; F:nucleosome binding; ISS:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB.
DR GO; GO:0033558; F:protein lysine deacetylase activity; ISO:MGI.
DR GO; GO:1904841; F:TORC2 complex binding; IDA:UniProtKB.
DR GO; GO:0003714; F:transcription corepressor activity; IGI:CACAO.
DR GO; GO:0008270; F:zinc ion binding; ISS:UniProtKB.
DR GO; GO:0006284; P:base-excision repair; IMP:CACAO.
DR GO; GO:0055007; P:cardiac muscle cell differentiation; IMP:UniProtKB.
DR GO; GO:0032922; P:circadian regulation of gene expression; IMP:UniProtKB.
DR GO; GO:0008340; P:determination of adult lifespan; IMP:UniProtKB.
DR GO; GO:0006281; P:DNA repair; IDA:UniProtKB.
DR GO; GO:0006302; P:double-strand break repair; ISS:UniProtKB.
DR GO; GO:0042593; P:glucose homeostasis; IMP:CACAO.
DR GO; GO:0070932; P:histone H3 deacetylation; IBA:GO_Central.
DR GO; GO:0042181; P:ketone biosynthetic process; IMP:UniProtKB.
DR GO; GO:0008285; P:negative regulation of cell population proliferation; IMP:CACAO.
DR GO; GO:2000773; P:negative regulation of cellular senescence; ISO:MGI.
DR GO; GO:0045814; P:negative regulation of gene expression, epigenetic; ISO:MGI.
DR GO; GO:0045721; P:negative regulation of gluconeogenesis; ISS:UniProtKB.
DR GO; GO:0046325; P:negative regulation of glucose import; IMP:CACAO.
DR GO; GO:0045820; P:negative regulation of glycolytic process; IMP:CACAO.
DR GO; GO:0042308; P:negative regulation of protein import into nucleus; IMP:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IMP:UniProtKB.
DR GO; GO:0034244; P:negative regulation of transcription elongation from RNA polymerase II promoter; IDA:UniProtKB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IMP:CACAO.
DR GO; GO:0010529; P:negative regulation of transposition; IDA:UniProtKB.
DR GO; GO:0031508; P:pericentric heterochromatin assembly; ISS:UniProtKB.
DR GO; GO:1905555; P:positive regulation of blood vessel branching; ISO:MGI.
DR GO; GO:1902732; P:positive regulation of chondrocyte proliferation; ISO:MGI.
DR GO; GO:0120162; P:positive regulation of cold-induced thermogenesis; IMP:UniProtKB.
DR GO; GO:2000781; P:positive regulation of double-strand break repair; IDA:UniProtKB.
DR GO; GO:0045600; P:positive regulation of fat cell differentiation; IMP:UniProtKB.
DR GO; GO:0048146; P:positive regulation of fibroblast proliferation; IMP:CACAO.
DR GO; GO:0032024; P:positive regulation of insulin secretion; IDA:UniProtKB.
DR GO; GO:0046827; P:positive regulation of protein export from nucleus; IDA:UniProtKB.
DR GO; GO:0120187; P:positive regulation of protein localization to chromatin; IMP:UniProtKB.
DR GO; GO:2000738; P:positive regulation of stem cell differentiation; IMP:UniProtKB.
DR GO; GO:2000648; P:positive regulation of stem cell proliferation; IMP:CACAO.
DR GO; GO:0032206; P:positive regulation of telomere maintenance; ISO:MGI.
DR GO; GO:1901485; P:positive regulation of transcription factor catabolic process; ISO:MGI.
DR GO; GO:1905564; P:positive regulation of vascular endothelial cell proliferation; ISO:MGI.
DR GO; GO:0003247; P:post-embryonic cardiac muscle cell growth involved in heart morphogenesis; ISO:MGI.
DR GO; GO:0006471; P:protein ADP-ribosylation; IDA:UniProtKB.
DR GO; GO:0006476; P:protein deacetylation; IMP:CACAO.
DR GO; GO:0051697; P:protein delipidation; ISS:UniProtKB.
DR GO; GO:0031648; P:protein destabilization; IMP:CACAO.
DR GO; GO:0042752; P:regulation of circadian rhythm; IMP:UniProtKB.
DR GO; GO:0010569; P:regulation of double-strand break repair via homologous recombination; ISS:UniProtKB.
DR GO; GO:0050994; P:regulation of lipid catabolic process; IMP:UniProtKB.
DR GO; GO:0019216; P:regulation of lipid metabolic process; IDA:UniProtKB.
DR GO; GO:0031667; P:response to nutrient levels; IEA:Ensembl.
DR GO; GO:0009411; P:response to UV; ISO:MGI.
DR GO; GO:0031509; P:subtelomeric heterochromatin assembly; ISO:MGI.
DR InterPro; IPR029035; DHS-like_NAD/FAD-binding_dom.
DR InterPro; IPR003000; Sirtuin.
DR InterPro; IPR026590; Ssirtuin_cat_dom.
DR Pfam; PF02146; SIR2; 2.
DR SUPFAM; SSF52467; SSF52467; 1.
DR PROSITE; PS50305; SIRTUIN; 1.
PE 1: Evidence at protein level;
KW Acetylation; Acyltransferase; Chromatin regulator; Chromosome;
KW Developmental protein; DNA damage; DNA repair; DNA-binding;
KW Endoplasmic reticulum; Glycosyltransferase; Isopeptide bond; Metal-binding;
KW NAD; Nucleotidyltransferase; Nucleus; Phosphoprotein; Reference proteome;
KW RNA-binding; Telomere; Transferase; Tumor suppressor; Ubl conjugation;
KW Zinc.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000250|UniProtKB:Q8N6T7"
FT CHAIN 2..334
FT /note="NAD-dependent protein deacylase sirtuin-6"
FT /id="PRO_0000110270"
FT DOMAIN 35..274
FT /note="Deacetylase sirtuin-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00236"
FT REGION 312..334
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 133
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00236,
FT ECO:0000305|PubMed:15795229, ECO:0000305|PubMed:19597350,
FT ECO:0000305|PubMed:31216030"
FT BINDING 53
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q8N6T7"
FT BINDING 57
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q8N6T7"
FT BINDING 64
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q8N6T7"
FT BINDING 65
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q8N6T7"
FT BINDING 71
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q8N6T7"
FT BINDING 113
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q8N6T7"
FT BINDING 133
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q8N6T7"
FT BINDING 141
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00236"
FT BINDING 144
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00236"
FT BINDING 166
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00236"
FT BINDING 177
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00236"
FT BINDING 214
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q8N6T7"
FT BINDING 216
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q8N6T7"
FT BINDING 240
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q8N6T7"
FT BINDING 242
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q8N6T7"
FT BINDING 258
FT /ligand="NAD(+)"
FT /ligand_id="ChEBI:CHEBI:57540"
FT /evidence="ECO:0000250|UniProtKB:Q8N6T7"
FT MOD_RES 2
FT /note="N-acetylserine"
FT /evidence="ECO:0000250|UniProtKB:Q8N6T7"
FT MOD_RES 10
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q8N6T7"
FT MOD_RES 33
FT /note="N6-acetyllysine"
FT /evidence="ECO:0000250|UniProtKB:Q8N6T7"
FT CROSSLNK 170
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q8N6T7"
FT MUTAGEN 56
FT /note="S->Y,A: Abolished NAD-dependent protein deacetylase,
FT defatty-acylase and mono-ADP-ribosyltransferase
FT activities."
FT /evidence="ECO:0000269|PubMed:15795229,
FT ECO:0000269|PubMed:25247314"
FT MUTAGEN 60
FT /note="G->A: Does not affect the NAD-dependent protein
FT defatty-acylase activity. Abolished NAD-dependent protein
FT deacetylase and mono-ADP-ribosyltransferase activities."
FT /evidence="ECO:0000269|PubMed:25247314,
FT ECO:0000269|PubMed:31216030"
FT MUTAGEN 63
FT /note="D->H: Embryonic lethality in knockin mice; mice fail
FT to form embryonic bodies and retain pluripotent gene
FT expression, leading to impaired embryonic stem cell
FT differentiation. Defects are caused by a failure to
FT deacetylate histone H3 at 'Lys-9' (H3K9)."
FT /evidence="ECO:0000269|PubMed:29555651"
FT MUTAGEN 65
FT /note="R->A: Does not affect the mono-ADP-
FT ribosyltransferase activity. Abolished NAD-dependent
FT protein deacetylase and defatty-acylase activities."
FT /evidence="ECO:0000269|PubMed:25247314,
FT ECO:0000269|PubMed:31216030"
FT MUTAGEN 133
FT /note="H->Y: Abolished NAD-dependent protein deacetylase,
FT deacylase and mono-ADP-ribosyltransferase activities."
FT /evidence="ECO:0000269|PubMed:15795229,
FT ECO:0000269|PubMed:19597350, ECO:0000269|PubMed:27457971,
FT ECO:0000269|PubMed:29599436, ECO:0000269|PubMed:31216030"
FT MUTAGEN 235
FT /note="R->K: Increased histone deacetylase activity,
FT ability to promote double-strand break (DSB) repair,
FT leading to increased life span; when associated with H-249
FT and 260-D--Q-264."
FT /evidence="ECO:0000269|PubMed:31002797"
FT MUTAGEN 249
FT /note="Q->H: Increased histone deacetylase activity,
FT ability to promote double-strand break (DSB) repair,
FT leading to increased life span; when associated with K-235
FT and 260-D--Q-264."
FT /evidence="ECO:0000269|PubMed:31002797"
FT MUTAGEN 260..264
FT /note="EVMCR->DVMTQ: Increased histone deacetylase
FT activity, ability to promote double-strand break (DSB)
FT repair, leading to increased life span; when associated
FT with K-235 and H-249."
FT /evidence="ECO:0000269|PubMed:31002797"
SQ SEQUENCE 334 AA; 36920 MW; 75FD950B42D68A1A CRC64;
MSVNYAAGLS PYADKGKCGL PEIFDPPEEL ERKVWELARL MWQSSSVVFH TGAGISTASG
IPDFRGPHGV WTMEERGLAP KFDTTFENAR PSKTHMALVQ LERMGFLSFL VSQNVDGLHV
RSGFPRDKLA ELHGNMFVEE CPKCKTQYVR DTVVGTMGLK ATGRLCTVAK TRGLRACRGE
LRDTILDWED SLPDRDLMLA DEASRTADLS VTLGTSLQIR PSGNLPLATK RRGGRLVIVN
LQPTKHDRQA DLRIHGYVDE VMCRLMKHLG LEIPAWDGPC VLDKALPPLP RPVALKAEPP
VHLNGAVHVS YKSKPNSPIL HRPPKRVKTE AAPS
