4kxq

Structural highlights

Function

SIR1_HUMAN NAD-dependent protein deacetylase that links transcriptional regulation directly to intracellular energetics and participates in the coordination of several separated cellular functions such as cell cycle, response to DNA damage, metobolism, apoptosis and autophagy. Can modulate chromatin function through deacetylation of histones and can promote alterations in the methylation of histones and DNA, leading to transcriptional repression. Deacetylates a broad range of transcription factors and coregulators, thereby regulating target gene expression positively and negatively. Serves as a sensor of the cytosolic ratio of NAD(+)/NADH which is altered by glucose deprivation and metabolic changes associated with caloric restriction. Is essential in skeletal muscle cell differentiation and in response to low nutrients mediates the inhibitory effect on skeletal myoblast differentiation which also involves 5'-AMP-activated protein kinase (AMPK) and nicotinamide phosphoribosyltransferase (NAMPT). Component of the eNoSC (energy-dependent nucleolar silencing) complex, a complex that mediates silencing of rDNA in response to intracellular energy status and acts by recruiting histone-modifying enzymes. The eNoSC complex is able to sense the energy status of cell: upon glucose starvation, elevation of NAD(+)/NADP(+) ratio activates SIRT1, leading to histone H3 deacetylation followed by dimethylation of H3 at 'Lys-9' (H3K9me2) by SUV39H1 and the formation of silent chromatin in the rDNA locus. Deacetylates 'Lys-266' of SUV39H1, leading to its activation. Inhibits skeletal muscle differentiation by deacetylating PCAF and MYOD1. Deacetylates H2A and 'Lys-26' of HIST1H1E. Deacetylates 'Lys-16' of histone H4 (in vitro). Involved in NR0B2/SHP corepression function through chromatin remodeling: Recruited to LRH1 target gene promoters by NR0B2/SHP thereby stimulating histone H3 and H4 deacetylation leading to transcriptional repression. Proposed to contribute to genomic integrity via positive regulation of telomere length; however, reports on localization to pericentromeric heterochromatin are conflicting. Proposed to play a role in constitutive heterochromatin (CH) formation and/or maintenance through regulation of the available pool of nuclear SUV39H1. Upon oxidative/metabolic stress decreases SUV39H1 degradation by inhibiting SUV39H1 polyubiquitination by MDM2. This increase in SUV39H1 levels enhances SUV39H1 turnover in CH, which in turn seems to accelerate renewal of the heterochromatin which correlates with greater genomic integrity during stress response. Deacetylates 'Lys-382' of p53/TP53 and impairs its ability to induce transcription-dependent proapoptotic program and modulate cell senescence. Deacetylates TAF1B and thereby represses rDNA transcription by the RNA polymerase I. Deacetylates MYC, promotes the association of MYC with MAX and decreases MYC stability leading to compromised transformational capability. Deacetylates FOXO3 in response to oxidative stress thereby increasing its ability to induce cell cycle arrest and resistance to oxidative stress but inhibiting FOXO3-mediated induction of apoptosis transcriptional activity; also leading to FOXO3 ubiquitination and protesomal degradation. Appears to have a similar effect on MLLT7/FOXO4 in regulation of transcriptional activity and apoptosis. Deacetylates DNMT1; thereby impairs DNMT1 methyltransferase-independent transcription repressor activity, modulates DNMT1 cell cycle regulatory function and DNMT1-mediated gene silencing. Deacetylates RELA/NF-kappa-B p65 thereby inhibiting its transactivating potential and augments apoptosis in response to TNF-alpha. Deacetylates HIF1A, KAT5/TIP60, RB1 and HIC1. Deacetylates FOXO1 resulting in its nuclear retention and enhancement of its transcriptional activity leading to increased gluconeogenesis in liver. Inhibits E2F1 transcriptional activity and apoptotic function, possibly by deacetylation. Involved in HES1- and HEY2-mediated transcriptional repression. In cooperation with MYCN seems to be involved in transcriptional repression of DUSP6/MAPK3 leading to MYCN stabilization by phosphorylation at 'Ser-62'. Deacetylates MEF2D. Required for antagonist-mediated transcription suppression of AR-dependent genes which may be linked to local deacetylation of histone H3. Represses HNF1A-mediated transcription. Required for the repression of ESRRG by CREBZF. Modulates AP-1 transcription factor activity. Deacetylates NR1H3 AND NR1H2 and deacetylation of NR1H3 at 'Lys-434' positively regulates transcription of NR1H3:RXR target genes, promotes NR1H3 proteosomal degradation and results in cholesterol efflux; a promoter clearing mechanism after reach round of transcription is proposed. Involved in lipid metabolism. Implicated in regulation of adipogenesis and fat mobilization in white adipocytes by repression of PPARG which probably involves association with NCOR1 and SMRT/NCOR2. Deacetylates ACSS2 leading to its activation, and HMGCS1. Involved in liver and muscle metabolism. Through deacteylation and activation of PPARGC1A is required to activate fatty acid oxidation in skeletel muscle under low-glucose conditions and is involved in glucose homeostasis. Involved in regulation of PPARA and fatty acid beta-oxidation in liver. Involved in positive regulation of insulin secretion in pancreatic beta cells in response to glucose; the function seems to imply transcriptional repression of UCP2. Proposed to deacetylate IRS2 thereby facilitating its insuline-induced tyrosine phosphorylation. Deacetylates SREBF1 isoform SREBP-1C thereby decreasing its stability and transactivation in lipogenic gene expression. Involved in DNA damage response by repressing genes which are involved in DNA repair, such as XPC and TP73, deacetylating XRCC6/Ku70, and faciliting recruitment of additional factors to sites of damaged DNA, such as SIRT1-deacetylated NBN can recruit ATM to initiate DNA repair and SIRT1-deacetylated XPA interacts with RPA2. Also involved in DNA repair of DNA double-strand breaks by homologous recombination and specifically single-strand annealing independently of XRCC6/Ku70 and NBN. Transcriptional suppression of XPC probably involves an E2F4:RBL2 suppressor complex and protein kinase B (AKT) signaling. Transcriptional suppression of TP73 probably involves E2F4 and PCAF. Deacetylates WRN thereby regulating its helicase and exonuclease activities and regulates WRN nuclear translocation in response to DNA damage. Deacetylates APEX1 at 'Lys-6' and 'Lys-7' and stimulates cellular AP endonuclease activity by promoting the association of APEX1 to XRCC1. Increases p53/TP53-mediated transcription-independent apoptosis by blocking nuclear translocation of cytoplasmic p53/TP53 and probably redirecting it to mitochondria. Deacetylates XRCC6/Ku70 at 'Lys-539' and 'Lys-542' causing it to sequester BAX away from mitochondria thereby inhibiting stress-induced apoptosis. Is involved in autophagy, presumably by deacetylating ATG5, ATG7 and MAP1LC3B/ATG8. Deacetylates AKT1 which leads to enhanced binding of AKT1 and PDK1 to PIP3 and promotes their activation. Proposed to play role in regulation of STK11/LBK1-dependent AMPK signaling pathways implicated in cellular senescence which seems to involve the regulation of the acetylation status of STK11/LBK1. Can deacetylate STK11/LBK1 and thereby increase its activity, cytoplasmic localization and association with STRAD; however, the relevance of such activity in normal cells is unclear. In endothelial cells is shown to inhibit STK11/LBK1 activity and to promote its degradation. Deacetylates SMAD7 at 'Lys-64' and 'Lys-70' thereby promoting its degradation. Deacetylates CIITA and augments its MHC class II transacivation and contributes to its stability. Deacteylates MECOM/EVI1. Isoform 2 is shown to deacetylate 'Lys-382' of p53/TP53, however with lower activity than isoform 1. In combination, the two isoforms exert an additive effect. Isoform 2 regulates p53/TP53 expression and cellular stress response and is in turn repressed by p53/TP53 presenting a SIRT1 isoform-dependent auto-regulatory loop. In case of HIV-1 infection, interacts with and deacetylates the viral Tat protein. The viral Tat protein inhibits SIRT1 deacetylation activity toward RELA/NF-kappa-B p65, thereby potentiates its transcriptional activity and SIRT1 is proposed to contribute to T-cell hyperactivation during infection. Deacetylates PML at 'Lys-487' and this deacetylation promotes PML control of PER2 nuclear localization.^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50]} SirtT1 75 kDa fragment: catalytically inactive 75SirT1 may be involved in regulation of apoptosis. May be involved in protecting chondrocytes from apoptotic death by associating with cytochrome C and interfering with apoptosome assembly.^{[51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] [73] [74] [75] [76] [77] [78] [79] [80] [81] [82] [83] [84] [85] [86] [87] [88] [89] [90] [91] [92] [93] [94] [95] [96] [97] [98] [99] [100]}

See Also

• Histone deacetylase 3D structures

References

1. ↑ Vaziri H, Dessain SK, Ng Eaton E, Imai SI, Frye RA, Pandita TK, Guarente L, Weinberg RA. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell. 2001 Oct 19;107(2):149-59. PMID:11672523
2. ↑ Langley E, Pearson M, Faretta M, Bauer UM, Frye RA, Minucci S, Pelicci PG, Kouzarides T. Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. EMBO J. 2002 May 15;21(10):2383-96. PMID:12006491 doi:10.1093/emboj/21.10.2383
3. ↑ Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA, Mayo MW. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 2004 Jun 16;23(12):2369-80. Epub 2004 May 20. PMID:15152190 doi:10.1038/sj.emboj.7600244
4. ↑ Motta MC, Divecha N, Lemieux M, Kamel C, Chen D, Gu W, Bultsma Y, McBurney M, Guarente L. Mammalian SIRT1 represses forkhead transcription factors. Cell. 2004 Feb 20;116(4):551-63. PMID:14980222
5. ↑ van der Horst A, Tertoolen LG, de Vries-Smits LM, Frye RA, Medema RH, Burgering BM. FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1). J Biol Chem. 2004 Jul 9;279(28):28873-9. Epub 2004 May 4. PMID:15126506 doi:10.1074/jbc.M401138200
6. ↑ Vaquero A, Scher M, Lee D, Erdjument-Bromage H, Tempst P, Reinberg D. Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. Mol Cell. 2004 Oct 8;16(1):93-105. PMID:15469825 doi:10.1016/j.molcel.2004.08.031
7. ↑ Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, Tran H, Ross SE, Mostoslavsky R, Cohen HY, Hu LS, Cheng HL, Jedrychowski MP, Gygi SP, Sinclair DA, Alt FW, Greenberg ME. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science. 2004 Mar 26;303(5666):2011-5. Epub 2004 Feb 19. PMID:14976264 doi:10.1126/science.1094637
8. ↑ Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science. 2004 Jul 16;305(5682):390-2. Epub 2004 Jun 17. PMID:15205477 doi:10.1126/science.1099196
9. ↑ Yang Y, Hou H, Haller EM, Nicosia SV, Bai W. Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation. EMBO J. 2005 Mar 9;24(5):1021-32. Epub 2005 Feb 3. PMID:15692560 doi:10.1038/sj.emboj.7600570
10. ↑ Michishita E, Park JY, Burneskis JM, Barrett JC, Horikawa I. Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol Biol Cell. 2005 Oct;16(10):4623-35. Epub 2005 Aug 3. PMID:16079181 doi:10.1091/mbc.E05-01-0033
11. ↑ Zhao X, Sternsdorf T, Bolger TA, Evans RM, Yao TP. Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications. Mol Cell Biol. 2005 Oct;25(19):8456-64. PMID:16166628 doi:25/19/8456
12. ↑ Wang C, Chen L, Hou X, Li Z, Kabra N, Ma Y, Nemoto S, Finkel T, Gu W, Cress WD, Chen J. Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage. Nat Cell Biol. 2006 Sep;8(9):1025-31. Epub 2006 Aug 6. PMID:16892051 doi:10.1038/ncb1468
13. ↑ Wong S, Weber JD. Deacetylation of the retinoblastoma tumour suppressor protein by SIRT1. Biochem J. 2007 Nov 1;407(3):451-60. PMID:17620057 doi:10.1042/BJ20070151
14. ↑ Jeong J, Juhn K, Lee H, Kim SH, Min BH, Lee KM, Cho MH, Park GH, Lee KH. SIRT1 promotes DNA repair activity and deacetylation of Ku70. Exp Mol Med. 2007 Feb 28;39(1):8-13. PMID:17334224 doi:10.1038/emm.2007.2
15. ↑ Dai JM, Wang ZY, Sun DC, Lin RX, Wang SQ. SIRT1 interacts with p73 and suppresses p73-dependent transcriptional activity. J Cell Physiol. 2007 Jan;210(1):161-6. PMID:16998810 doi:10.1002/jcp.20831
16. ↑ Dai Y, Ngo D, Forman LW, Qin DC, Jacob J, Faller DV. Sirtuin 1 is required for antagonist-induced transcriptional repression of androgen-responsive genes by the androgen receptor. Mol Endocrinol. 2007 Aug;21(8):1807-21. Epub 2007 May 15. PMID:17505061 doi:10.1210/me.2006-0467
17. ↑ Li X, Zhang S, Blander G, Tse JG, Krieger M, Guarente L. SIRT1 deacetylates and positively regulates the nuclear receptor LXR. Mol Cell. 2007 Oct 12;28(1):91-106. PMID:17936707 doi:10.1016/j.molcel.2007.07.032
18. ↑ Yuan Z, Zhang X, Sengupta N, Lane WS, Seto E. SIRT1 regulates the function of the Nijmegen breakage syndrome protein. Mol Cell. 2007 Jul 6;27(1):149-62. PMID:17612497 doi:10.1016/j.molcel.2007.05.029
19. ↑ Stankovic-Valentin N, Deltour S, Seeler J, Pinte S, Vergoten G, Guerardel C, Dejean A, Leprince D. An acetylation/deacetylation-SUMOylation switch through a phylogenetically conserved psiKXEP motif in the tumor suppressor HIC1 regulates transcriptional repression activity. Mol Cell Biol. 2007 Apr;27(7):2661-75. Epub 2007 Feb 5. PMID:17283066 doi:MCB.01098-06
20. ↑ Murayama A, Ohmori K, Fujimura A, Minami H, Yasuzawa-Tanaka K, Kuroda T, Oie S, Daitoku H, Okuwaki M, Nagata K, Fukamizu A, Kimura K, Shimizu T, Yanagisawa J. Epigenetic control of rDNA loci in response to intracellular energy status. Cell. 2008 May 16;133(4):627-39. PMID:18485871 doi:S0092-8674(08)00459-5
21. ↑ Kwon HS, Brent MM, Getachew R, Jayakumar P, Chen LF, Schnolzer M, McBurney MW, Marmorstein R, Greene WC, Ott M. Human immunodeficiency virus type 1 Tat protein inhibits the SIRT1 deacetylase and induces T cell hyperactivation. Cell Host Microbe. 2008 Mar 13;3(3):158-67. doi: 10.1016/j.chom.2008.02.002. PMID:18329615 doi:10.1016/j.chom.2008.02.002
22. ↑ Li K, Casta A, Wang R, Lozada E, Fan W, Kane S, Ge Q, Gu W, Orren D, Luo J. Regulation of WRN protein cellular localization and enzymatic activities by SIRT1-mediated deacetylation. J Biol Chem. 2008 Mar 21;283(12):7590-8. doi: 10.1074/jbc.M709707200. Epub 2008, Jan 17. PMID:18203716 doi:10.1074/jbc.M709707200
23. ↑ Lan F, Cacicedo JM, Ruderman N, Ido Y. SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J Biol Chem. 2008 Oct 10;283(41):27628-35. doi: 10.1074/jbc.M805711200. Epub 2008, Aug 7. PMID:18687677 doi:10.1074/jbc.M805711200
24. ↑ Lee IH, Cao L, Mostoslavsky R, Lombard DB, Liu J, Bruns NE, Tsokos M, Alt FW, Finkel T. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3374-9. doi: 10.1073/pnas.0712145105., Epub 2008 Feb 22. PMID:18296641 doi:10.1073/pnas.0712145105
25. ↑ Du J, Jiang H, Lin H. Investigating the ADP-ribosyltransferase activity of sirtuins with NAD analogues and 32P-NAD. Biochemistry. 2009 Apr 7;48(13):2878-90. doi: 10.1021/bi802093g. PMID:19220062 doi:10.1021/bi802093g
26. ↑ Xie YB, Park JH, Kim DK, Hwang JH, Oh S, Park SB, Shong M, Lee IK, Choi HS. Transcriptional corepressor SMILE recruits SIRT1 to inhibit nuclear receptor estrogen receptor-related receptor gamma transactivation. J Biol Chem. 2009 Oct 16;284(42):28762-74. doi: 10.1074/jbc.M109.034165. Epub, 2009 Aug 18. PMID:19690166 doi:10.1074/jbc.M109.034165
27. ↑ Yuan J, Minter-Dykhouse K, Lou Z. A c-Myc-SIRT1 feedback loop regulates cell growth and transformation. J Cell Biol. 2009 Apr 20;185(2):203-11. doi: 10.1083/jcb.200809167. Epub 2009 Apr, 13. PMID:19364925 doi:10.1083/jcb.200809167
28. ↑ Pediconi N, Guerrieri F, Vossio S, Bruno T, Belloni L, Schinzari V, Scisciani C, Fanciulli M, Levrero M. hSirT1-dependent regulation of the PCAF-E2F1-p73 apoptotic pathway in response to DNA damage. Mol Cell Biol. 2009 Apr;29(8):1989-98. doi: 10.1128/MCB.00552-08. Epub 2009 Feb, 2. PMID:19188449 doi:10.1128/MCB.00552-08
29. ↑ Zu Y, Liu L, Lee MY, Xu C, Liang Y, Man RY, Vanhoutte PM, Wang Y. SIRT1 promotes proliferation and prevents senescence through targeting LKB1 in primary porcine aortic endothelial cells. Circ Res. 2010 Apr 30;106(8):1384-93. doi: 10.1161/CIRCRESAHA.109.215483. Epub, 2010 Mar 4. PMID:20203304 doi:10.1161/CIRCRESAHA.109.215483
30. ↑ Uhl M, Csernok A, Aydin S, Kreienberg R, Wiesmuller L, Gatz SA. Role of SIRT1 in homologous recombination. DNA Repair (Amst). 2010 Apr 4;9(4):383-93. doi: 10.1016/j.dnarep.2009.12.020., Epub 2010 Jan 25. PMID:20097625 doi:10.1016/j.dnarep.2009.12.020
31. ↑ Wang J, Chen J. SIRT1 regulates autoacetylation and histone acetyltransferase activity of TIP60. J Biol Chem. 2010 Apr 9;285(15):11458-64. doi: 10.1074/jbc.M109.087585. Epub 2010, Jan 25. PMID:20100829 doi:10.1074/jbc.M109.087585
32. ↑ Ponugoti B, Kim DH, Xiao Z, Smith Z, Miao J, Zang M, Wu SY, Chiang CM, Veenstra TD, Kemper JK. SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism. J Biol Chem. 2010 Oct 29;285(44):33959-70. doi: 10.1074/jbc.M110.122978. Epub, 2010 Sep 3. PMID:20817729 doi:10.1074/jbc.M110.122978
33. ↑ Lim JH, Lee YM, Chun YS, Chen J, Kim JE, Park JW. Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. Mol Cell. 2010 Jun 25;38(6):864-78. doi: 10.1016/j.molcel.2010.05.023. PMID:20620956 doi:10.1016/j.molcel.2010.05.023
34. ↑ Fan W, Luo J. SIRT1 regulates UV-induced DNA repair through deacetylating XPA. Mol Cell. 2010 Jul 30;39(2):247-58. doi: 10.1016/j.molcel.2010.07.006. PMID:20670893 doi:10.1016/j.molcel.2010.07.006
35. ↑ Yamamori T, DeRicco J, Naqvi A, Hoffman TA, Mattagajasingh I, Kasuno K, Jung SB, Kim CS, Irani K. SIRT1 deacetylates APE1 and regulates cellular base excision repair. Nucleic Acids Res. 2010 Jan;38(3):832-45. doi: 10.1093/nar/gkp1039. Epub 2009 Nov, 24. PMID:19934257 doi:10.1093/nar/gkp1039
36. ↑ Chanda D, Xie YB, Choi HS. Transcriptional corepressor SHP recruits SIRT1 histone deacetylase to inhibit LRH-1 transactivation. Nucleic Acids Res. 2010 Aug;38(14):4607-19. doi: 10.1093/nar/gkq227. Epub 2010, Apr 7. PMID:20375098 doi:10.1093/nar/gkq227
37. ↑ Lynch CJ, Shah ZH, Allison SJ, Ahmed SU, Ford J, Warnock LJ, Li H, Serrano M, Milner J. SIRT1 undergoes alternative splicing in a novel auto-regulatory loop with p53. PLoS One. 2010 Oct 21;5(10):e13502. doi: 10.1371/journal.pone.0013502. PMID:20975832 doi:10.1371/journal.pone.0013502
38. ↑ Ming M, Shea CR, Guo X, Li X, Soltani K, Han W, He YY. Regulation of global genome nucleotide excision repair by SIRT1 through xeroderma pigmentosum C. Proc Natl Acad Sci U S A. 2010 Dec 28;107(52):22623-8. doi:, 10.1073/pnas.1010377108. Epub 2010 Dec 13. PMID:21149730 doi:10.1073/pnas.1010377108
39. ↑ Hirschey MD, Shimazu T, Capra JA, Pollard KS, Verdin E. SIRT1 and SIRT3 deacetylate homologous substrates: AceCS1,2 and HMGCS1,2. Aging (Albany NY). 2011 Jun;3(6):635-42. PMID:21701047
40. ↑ Pradhan AK, Kuila N, Singh S, Chakraborty S. EVI1 up-regulates the stress responsive gene SIRT1 which triggers deacetylation and degradation of EVI1. Biochim Biophys Acta. 2011 Apr-Jun;1809(4-6):269-75. doi:, 10.1016/j.bbagrm.2011.04.007. Epub 2011 Apr 30. PMID:21555002 doi:10.1016/j.bbagrm.2011.04.007
41. ↑ Mao B, Zhao G, Lv X, Chen HZ, Xue Z, Yang B, Liu DP, Liang CC. Sirt1 deacetylates c-Myc and promotes c-Myc/Max association. Int J Biochem Cell Biol. 2011 Nov;43(11):1573-81. doi:, 10.1016/j.biocel.2011.07.006. Epub 2011 Jul 22. PMID:21807113 doi:10.1016/j.biocel.2011.07.006
42. ↑ Back JH, Rezvani HR, Zhu Y, Guyonnet-Duperat V, Athar M, Ratner D, Kim AL. Cancer cell survival following DNA damage-mediated premature senescence is regulated by mammalian target of rapamycin (mTOR)-dependent Inhibition of sirtuin 1. J Biol Chem. 2011 May 27;286(21):19100-8. doi: 10.1074/jbc.M111.240598. Epub 2011, Apr 6. PMID:21471201 doi:10.1074/jbc.M111.240598
43. ↑ Bosch-Presegue L, Raurell-Vila H, Marazuela-Duque A, Kane-Goldsmith N, Valle A, Oliver J, Serrano L, Vaquero A. Stabilization of Suv39H1 by SirT1 is part of oxidative stress response and ensures genome protection. Mol Cell. 2011 Apr 22;42(2):210-23. doi: 10.1016/j.molcel.2011.02.034. PMID:21504832 doi:10.1016/j.molcel.2011.02.034
44. ↑ Peng L, Yuan Z, Ling H, Fukasawa K, Robertson K, Olashaw N, Koomen J, Chen J, Lane WS, Seto E. SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) protein and alters its activities. Mol Cell Biol. 2011 Dec;31(23):4720-34. doi: 10.1128/MCB.06147-11. Epub 2011 Sep , 26. PMID:21947282 doi:10.1128/MCB.06147-11
45. ↑ Marshall GM, Liu PY, Gherardi S, Scarlett CJ, Bedalov A, Xu N, Iraci N, Valli E, Ling D, Thomas W, van Bekkum M, Sekyere E, Jankowski K, Trahair T, Mackenzie KL, Haber M, Norris MD, Biankin AV, Perini G, Liu T. SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability. PLoS Genet. 2011 Jun;7(6):e1002135. doi: 10.1371/journal.pgen.1002135. Epub 2011 , Jun 16. PMID:21698133 doi:10.1371/journal.pgen.1002135
46. ↑ Sundaresan NR, Pillai VB, Wolfgeher D, Samant S, Vasudevan P, Parekh V, Raghuraman H, Cunningham JM, Gupta M, Gupta MP. The deacetylase SIRT1 promotes membrane localization and activation of Akt and PDK1 during tumorigenesis and cardiac hypertrophy. Sci Signal. 2011 Jul 19;4(182):ra46. doi: 10.1126/scisignal.2001465. PMID:21775285 doi:10.1126/scisignal.2001465
47. ↑ Oppenheimer H, Gabay O, Meir H, Haze A, Kandel L, Liebergall M, Gagarina V, Lee EJ, Dvir-Ginzberg M. 75-kd sirtuin 1 blocks tumor necrosis factor alpha-mediated apoptosis in human osteoarthritic chondrocytes. Arthritis Rheum. 2012 Mar;64(3):718-28. doi: 10.1002/art.33407. PMID:21987377 doi:10.1002/art.33407
48. ↑ Wu X, Kong X, Chen D, Li H, Zhao Y, Xia M, Fang M, Li P, Fang F, Sun L, Tian W, Xu H, Yang Y, Qi X, Gao Y, Sha J, Chen Q, Xu Y. SIRT1 links CIITA deacetylation to MHC II activation. Nucleic Acids Res. 2011 Dec;39(22):9549-58. doi: 10.1093/nar/gkr651. Epub 2011, Sep 2. PMID:21890893 doi:10.1093/nar/gkr651
49. ↑ Miki T, Xu Z, Chen-Goodspeed M, Liu M, Van Oort-Jansen A, Rea MA, Zhao Z, Lee CC, Chang KS. PML regulates PER2 nuclear localization and circadian function. EMBO J. 2012 Mar 21;31(6):1427-39. doi: 10.1038/emboj.2012.1. Epub 2012 Jan 24. PMID:22274616 doi:10.1038/emboj.2012.1
50. ↑ Wang F, Chan CH, Chen K, Guan X, Lin HK, Tong Q. Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation. Oncogene. 2012 Mar 22;31(12):1546-57. doi: 10.1038/onc.2011.347. Epub 2011 Aug, 15. PMID:21841822 doi:10.1038/onc.2011.347
51. ↑ Vaziri H, Dessain SK, Ng Eaton E, Imai SI, Frye RA, Pandita TK, Guarente L, Weinberg RA. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell. 2001 Oct 19;107(2):149-59. PMID:11672523
52. ↑ Langley E, Pearson M, Faretta M, Bauer UM, Frye RA, Minucci S, Pelicci PG, Kouzarides T. Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. EMBO J. 2002 May 15;21(10):2383-96. PMID:12006491 doi:10.1093/emboj/21.10.2383
53. ↑ Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA, Mayo MW. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 2004 Jun 16;23(12):2369-80. Epub 2004 May 20. PMID:15152190 doi:10.1038/sj.emboj.7600244
54. ↑ Motta MC, Divecha N, Lemieux M, Kamel C, Chen D, Gu W, Bultsma Y, McBurney M, Guarente L. Mammalian SIRT1 represses forkhead transcription factors. Cell. 2004 Feb 20;116(4):551-63. PMID:14980222
55. ↑ van der Horst A, Tertoolen LG, de Vries-Smits LM, Frye RA, Medema RH, Burgering BM. FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1). J Biol Chem. 2004 Jul 9;279(28):28873-9. Epub 2004 May 4. PMID:15126506 doi:10.1074/jbc.M401138200
56. ↑ Vaquero A, Scher M, Lee D, Erdjument-Bromage H, Tempst P, Reinberg D. Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. Mol Cell. 2004 Oct 8;16(1):93-105. PMID:15469825 doi:10.1016/j.molcel.2004.08.031
57. ↑ Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, Tran H, Ross SE, Mostoslavsky R, Cohen HY, Hu LS, Cheng HL, Jedrychowski MP, Gygi SP, Sinclair DA, Alt FW, Greenberg ME. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science. 2004 Mar 26;303(5666):2011-5. Epub 2004 Feb 19. PMID:14976264 doi:10.1126/science.1094637
58. ↑ Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science. 2004 Jul 16;305(5682):390-2. Epub 2004 Jun 17. PMID:15205477 doi:10.1126/science.1099196
59. ↑ Yang Y, Hou H, Haller EM, Nicosia SV, Bai W. Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation. EMBO J. 2005 Mar 9;24(5):1021-32. Epub 2005 Feb 3. PMID:15692560 doi:10.1038/sj.emboj.7600570
60. ↑ Michishita E, Park JY, Burneskis JM, Barrett JC, Horikawa I. Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol Biol Cell. 2005 Oct;16(10):4623-35. Epub 2005 Aug 3. PMID:16079181 doi:10.1091/mbc.E05-01-0033
61. ↑ Zhao X, Sternsdorf T, Bolger TA, Evans RM, Yao TP. Regulation of MEF2 by histone deacetylase 4- and SIRT1 deacetylase-mediated lysine modifications. Mol Cell Biol. 2005 Oct;25(19):8456-64. PMID:16166628 doi:25/19/8456
62. ↑ Wang C, Chen L, Hou X, Li Z, Kabra N, Ma Y, Nemoto S, Finkel T, Gu W, Cress WD, Chen J. Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage. Nat Cell Biol. 2006 Sep;8(9):1025-31. Epub 2006 Aug 6. PMID:16892051 doi:10.1038/ncb1468
63. ↑ Wong S, Weber JD. Deacetylation of the retinoblastoma tumour suppressor protein by SIRT1. Biochem J. 2007 Nov 1;407(3):451-60. PMID:17620057 doi:10.1042/BJ20070151
64. ↑ Jeong J, Juhn K, Lee H, Kim SH, Min BH, Lee KM, Cho MH, Park GH, Lee KH. SIRT1 promotes DNA repair activity and deacetylation of Ku70. Exp Mol Med. 2007 Feb 28;39(1):8-13. PMID:17334224 doi:10.1038/emm.2007.2
65. ↑ Dai JM, Wang ZY, Sun DC, Lin RX, Wang SQ. SIRT1 interacts with p73 and suppresses p73-dependent transcriptional activity. J Cell Physiol. 2007 Jan;210(1):161-6. PMID:16998810 doi:10.1002/jcp.20831
66. ↑ Dai Y, Ngo D, Forman LW, Qin DC, Jacob J, Faller DV. Sirtuin 1 is required for antagonist-induced transcriptional repression of androgen-responsive genes by the androgen receptor. Mol Endocrinol. 2007 Aug;21(8):1807-21. Epub 2007 May 15. PMID:17505061 doi:10.1210/me.2006-0467
67. ↑ Li X, Zhang S, Blander G, Tse JG, Krieger M, Guarente L. SIRT1 deacetylates and positively regulates the nuclear receptor LXR. Mol Cell. 2007 Oct 12;28(1):91-106. PMID:17936707 doi:10.1016/j.molcel.2007.07.032
68. ↑ Yuan Z, Zhang X, Sengupta N, Lane WS, Seto E. SIRT1 regulates the function of the Nijmegen breakage syndrome protein. Mol Cell. 2007 Jul 6;27(1):149-62. PMID:17612497 doi:10.1016/j.molcel.2007.05.029
69. ↑ Stankovic-Valentin N, Deltour S, Seeler J, Pinte S, Vergoten G, Guerardel C, Dejean A, Leprince D. An acetylation/deacetylation-SUMOylation switch through a phylogenetically conserved psiKXEP motif in the tumor suppressor HIC1 regulates transcriptional repression activity. Mol Cell Biol. 2007 Apr;27(7):2661-75. Epub 2007 Feb 5. PMID:17283066 doi:MCB.01098-06
70. ↑ Murayama A, Ohmori K, Fujimura A, Minami H, Yasuzawa-Tanaka K, Kuroda T, Oie S, Daitoku H, Okuwaki M, Nagata K, Fukamizu A, Kimura K, Shimizu T, Yanagisawa J. Epigenetic control of rDNA loci in response to intracellular energy status. Cell. 2008 May 16;133(4):627-39. PMID:18485871 doi:S0092-8674(08)00459-5
71. ↑ Kwon HS, Brent MM, Getachew R, Jayakumar P, Chen LF, Schnolzer M, McBurney MW, Marmorstein R, Greene WC, Ott M. Human immunodeficiency virus type 1 Tat protein inhibits the SIRT1 deacetylase and induces T cell hyperactivation. Cell Host Microbe. 2008 Mar 13;3(3):158-67. doi: 10.1016/j.chom.2008.02.002. PMID:18329615 doi:10.1016/j.chom.2008.02.002
72. ↑ Li K, Casta A, Wang R, Lozada E, Fan W, Kane S, Ge Q, Gu W, Orren D, Luo J. Regulation of WRN protein cellular localization and enzymatic activities by SIRT1-mediated deacetylation. J Biol Chem. 2008 Mar 21;283(12):7590-8. doi: 10.1074/jbc.M709707200. Epub 2008, Jan 17. PMID:18203716 doi:10.1074/jbc.M709707200
73. ↑ Lan F, Cacicedo JM, Ruderman N, Ido Y. SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J Biol Chem. 2008 Oct 10;283(41):27628-35. doi: 10.1074/jbc.M805711200. Epub 2008, Aug 7. PMID:18687677 doi:10.1074/jbc.M805711200
74. ↑ Lee IH, Cao L, Mostoslavsky R, Lombard DB, Liu J, Bruns NE, Tsokos M, Alt FW, Finkel T. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3374-9. doi: 10.1073/pnas.0712145105., Epub 2008 Feb 22. PMID:18296641 doi:10.1073/pnas.0712145105
75. ↑ Du J, Jiang H, Lin H. Investigating the ADP-ribosyltransferase activity of sirtuins with NAD analogues and 32P-NAD. Biochemistry. 2009 Apr 7;48(13):2878-90. doi: 10.1021/bi802093g. PMID:19220062 doi:10.1021/bi802093g
76. ↑ Xie YB, Park JH, Kim DK, Hwang JH, Oh S, Park SB, Shong M, Lee IK, Choi HS. Transcriptional corepressor SMILE recruits SIRT1 to inhibit nuclear receptor estrogen receptor-related receptor gamma transactivation. J Biol Chem. 2009 Oct 16;284(42):28762-74. doi: 10.1074/jbc.M109.034165. Epub, 2009 Aug 18. PMID:19690166 doi:10.1074/jbc.M109.034165
77. ↑ Yuan J, Minter-Dykhouse K, Lou Z. A c-Myc-SIRT1 feedback loop regulates cell growth and transformation. J Cell Biol. 2009 Apr 20;185(2):203-11. doi: 10.1083/jcb.200809167. Epub 2009 Apr, 13. PMID:19364925 doi:10.1083/jcb.200809167
78. ↑ Pediconi N, Guerrieri F, Vossio S, Bruno T, Belloni L, Schinzari V, Scisciani C, Fanciulli M, Levrero M. hSirT1-dependent regulation of the PCAF-E2F1-p73 apoptotic pathway in response to DNA damage. Mol Cell Biol. 2009 Apr;29(8):1989-98. doi: 10.1128/MCB.00552-08. Epub 2009 Feb, 2. PMID:19188449 doi:10.1128/MCB.00552-08
79. ↑ Zu Y, Liu L, Lee MY, Xu C, Liang Y, Man RY, Vanhoutte PM, Wang Y. SIRT1 promotes proliferation and prevents senescence through targeting LKB1 in primary porcine aortic endothelial cells. Circ Res. 2010 Apr 30;106(8):1384-93. doi: 10.1161/CIRCRESAHA.109.215483. Epub, 2010 Mar 4. PMID:20203304 doi:10.1161/CIRCRESAHA.109.215483
80. ↑ Uhl M, Csernok A, Aydin S, Kreienberg R, Wiesmuller L, Gatz SA. Role of SIRT1 in homologous recombination. DNA Repair (Amst). 2010 Apr 4;9(4):383-93. doi: 10.1016/j.dnarep.2009.12.020., Epub 2010 Jan 25. PMID:20097625 doi:10.1016/j.dnarep.2009.12.020
81. ↑ Wang J, Chen J. SIRT1 regulates autoacetylation and histone acetyltransferase activity of TIP60. J Biol Chem. 2010 Apr 9;285(15):11458-64. doi: 10.1074/jbc.M109.087585. Epub 2010, Jan 25. PMID:20100829 doi:10.1074/jbc.M109.087585
82. ↑ Ponugoti B, Kim DH, Xiao Z, Smith Z, Miao J, Zang M, Wu SY, Chiang CM, Veenstra TD, Kemper JK. SIRT1 deacetylates and inhibits SREBP-1C activity in regulation of hepatic lipid metabolism. J Biol Chem. 2010 Oct 29;285(44):33959-70. doi: 10.1074/jbc.M110.122978. Epub, 2010 Sep 3. PMID:20817729 doi:10.1074/jbc.M110.122978
83. ↑ Lim JH, Lee YM, Chun YS, Chen J, Kim JE, Park JW. Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. Mol Cell. 2010 Jun 25;38(6):864-78. doi: 10.1016/j.molcel.2010.05.023. PMID:20620956 doi:10.1016/j.molcel.2010.05.023
84. ↑ Fan W, Luo J. SIRT1 regulates UV-induced DNA repair through deacetylating XPA. Mol Cell. 2010 Jul 30;39(2):247-58. doi: 10.1016/j.molcel.2010.07.006. PMID:20670893 doi:10.1016/j.molcel.2010.07.006
85. ↑ Yamamori T, DeRicco J, Naqvi A, Hoffman TA, Mattagajasingh I, Kasuno K, Jung SB, Kim CS, Irani K. SIRT1 deacetylates APE1 and regulates cellular base excision repair. Nucleic Acids Res. 2010 Jan;38(3):832-45. doi: 10.1093/nar/gkp1039. Epub 2009 Nov, 24. PMID:19934257 doi:10.1093/nar/gkp1039
86. ↑ Chanda D, Xie YB, Choi HS. Transcriptional corepressor SHP recruits SIRT1 histone deacetylase to inhibit LRH-1 transactivation. Nucleic Acids Res. 2010 Aug;38(14):4607-19. doi: 10.1093/nar/gkq227. Epub 2010, Apr 7. PMID:20375098 doi:10.1093/nar/gkq227
87. ↑ Lynch CJ, Shah ZH, Allison SJ, Ahmed SU, Ford J, Warnock LJ, Li H, Serrano M, Milner J. SIRT1 undergoes alternative splicing in a novel auto-regulatory loop with p53. PLoS One. 2010 Oct 21;5(10):e13502. doi: 10.1371/journal.pone.0013502. PMID:20975832 doi:10.1371/journal.pone.0013502
88. ↑ Ming M, Shea CR, Guo X, Li X, Soltani K, Han W, He YY. Regulation of global genome nucleotide excision repair by SIRT1 through xeroderma pigmentosum C. Proc Natl Acad Sci U S A. 2010 Dec 28;107(52):22623-8. doi:, 10.1073/pnas.1010377108. Epub 2010 Dec 13. PMID:21149730 doi:10.1073/pnas.1010377108
89. ↑ Hirschey MD, Shimazu T, Capra JA, Pollard KS, Verdin E. SIRT1 and SIRT3 deacetylate homologous substrates: AceCS1,2 and HMGCS1,2. Aging (Albany NY). 2011 Jun;3(6):635-42. PMID:21701047
90. ↑ Pradhan AK, Kuila N, Singh S, Chakraborty S. EVI1 up-regulates the stress responsive gene SIRT1 which triggers deacetylation and degradation of EVI1. Biochim Biophys Acta. 2011 Apr-Jun;1809(4-6):269-75. doi:, 10.1016/j.bbagrm.2011.04.007. Epub 2011 Apr 30. PMID:21555002 doi:10.1016/j.bbagrm.2011.04.007
91. ↑ Mao B, Zhao G, Lv X, Chen HZ, Xue Z, Yang B, Liu DP, Liang CC. Sirt1 deacetylates c-Myc and promotes c-Myc/Max association. Int J Biochem Cell Biol. 2011 Nov;43(11):1573-81. doi:, 10.1016/j.biocel.2011.07.006. Epub 2011 Jul 22. PMID:21807113 doi:10.1016/j.biocel.2011.07.006
92. ↑ Back JH, Rezvani HR, Zhu Y, Guyonnet-Duperat V, Athar M, Ratner D, Kim AL. Cancer cell survival following DNA damage-mediated premature senescence is regulated by mammalian target of rapamycin (mTOR)-dependent Inhibition of sirtuin 1. J Biol Chem. 2011 May 27;286(21):19100-8. doi: 10.1074/jbc.M111.240598. Epub 2011, Apr 6. PMID:21471201 doi:10.1074/jbc.M111.240598
93. ↑ Bosch-Presegue L, Raurell-Vila H, Marazuela-Duque A, Kane-Goldsmith N, Valle A, Oliver J, Serrano L, Vaquero A. Stabilization of Suv39H1 by SirT1 is part of oxidative stress response and ensures genome protection. Mol Cell. 2011 Apr 22;42(2):210-23. doi: 10.1016/j.molcel.2011.02.034. PMID:21504832 doi:10.1016/j.molcel.2011.02.034
94. ↑ Peng L, Yuan Z, Ling H, Fukasawa K, Robertson K, Olashaw N, Koomen J, Chen J, Lane WS, Seto E. SIRT1 deacetylates the DNA methyltransferase 1 (DNMT1) protein and alters its activities. Mol Cell Biol. 2011 Dec;31(23):4720-34. doi: 10.1128/MCB.06147-11. Epub 2011 Sep , 26. PMID:21947282 doi:10.1128/MCB.06147-11
95. ↑ Marshall GM, Liu PY, Gherardi S, Scarlett CJ, Bedalov A, Xu N, Iraci N, Valli E, Ling D, Thomas W, van Bekkum M, Sekyere E, Jankowski K, Trahair T, Mackenzie KL, Haber M, Norris MD, Biankin AV, Perini G, Liu T. SIRT1 promotes N-Myc oncogenesis through a positive feedback loop involving the effects of MKP3 and ERK on N-Myc protein stability. PLoS Genet. 2011 Jun;7(6):e1002135. doi: 10.1371/journal.pgen.1002135. Epub 2011 , Jun 16. PMID:21698133 doi:10.1371/journal.pgen.1002135
96. ↑ Sundaresan NR, Pillai VB, Wolfgeher D, Samant S, Vasudevan P, Parekh V, Raghuraman H, Cunningham JM, Gupta M, Gupta MP. The deacetylase SIRT1 promotes membrane localization and activation of Akt and PDK1 during tumorigenesis and cardiac hypertrophy. Sci Signal. 2011 Jul 19;4(182):ra46. doi: 10.1126/scisignal.2001465. PMID:21775285 doi:10.1126/scisignal.2001465
97. ↑ Oppenheimer H, Gabay O, Meir H, Haze A, Kandel L, Liebergall M, Gagarina V, Lee EJ, Dvir-Ginzberg M. 75-kd sirtuin 1 blocks tumor necrosis factor alpha-mediated apoptosis in human osteoarthritic chondrocytes. Arthritis Rheum. 2012 Mar;64(3):718-28. doi: 10.1002/art.33407. PMID:21987377 doi:10.1002/art.33407
98. ↑ Wu X, Kong X, Chen D, Li H, Zhao Y, Xia M, Fang M, Li P, Fang F, Sun L, Tian W, Xu H, Yang Y, Qi X, Gao Y, Sha J, Chen Q, Xu Y. SIRT1 links CIITA deacetylation to MHC II activation. Nucleic Acids Res. 2011 Dec;39(22):9549-58. doi: 10.1093/nar/gkr651. Epub 2011, Sep 2. PMID:21890893 doi:10.1093/nar/gkr651
99. ↑ Miki T, Xu Z, Chen-Goodspeed M, Liu M, Van Oort-Jansen A, Rea MA, Zhao Z, Lee CC, Chang KS. PML regulates PER2 nuclear localization and circadian function. EMBO J. 2012 Mar 21;31(6):1427-39. doi: 10.1038/emboj.2012.1. Epub 2012 Jan 24. PMID:22274616 doi:10.1038/emboj.2012.1
100. ↑ Wang F, Chan CH, Chen K, Guan X, Lin HK, Tong Q. Deacetylation of FOXO3 by SIRT1 or SIRT2 leads to Skp2-mediated FOXO3 ubiquitination and degradation. Oncogene. 2012 Mar 22;31(12):1546-57. doi: 10.1038/onc.2011.347. Epub 2011 Aug, 15. PMID:21841822 doi:10.1038/onc.2011.347
101. ↑ Davenport AM, Huber FM, Hoelz A. Structural and Functional Analysis of Human SIRT1. J Mol Biol. 2013 Oct 10. pii: S0022-2836(13)00635-9. doi:, 10.1016/j.jmb.2013.10.009. PMID:24120939 doi:http://dx.doi.org/10.1016/j.jmb.2013.10.009