[KSCI] Korea Science Citation Index Service

http://dx.doi.org/10.1007/s10059-009-0169-x

Sirtuin/Sir2 Phylogeny, Evolutionary Considerations and Structural Conservation

Greiss, Sebastian (Wellcome Trust Centre for Gene Regulation and Expression, University of Dundee)
Gartner, Anton (Wellcome Trust Centre for Gene Regulation and Expression, University of Dundee)

Publication Information

Abstract

The sirtuins are a protein family named after the first identified member, S. cerevisiae Sir2p. Sirtuins are protein deacetylases whose activity is dependent on $NAD^+$ as a cosubstrate. They are structurally defined by two central domains that together form a highly conserved catalytic center, which catalyzes the transfer of an acetyl moiety from acetyllysine to $NAD^+$ , yielding nicotinamide, the unique metabolite O-acetyl-ADP-ribose and deacetylated lysine. One or more sirtuins are present in virtually all species from bacteria to mammals. Here we describe a phylogenetic analysis of sirtuins. Based on their phylogenetic relationship, sirtuins can be grouped into over a dozen classes and subclasses. Humans, like most vertebrates, have seven sirtuins: SIRT1-SIRT7. These function in diverse cellular pathways, regulating transcriptional repression, aging, metabolism, DNA damage responses and apoptosis. We show that these seven sirtuins arose early during animal evolution. Conserved residues cluster around the catalytic center of known sirtuin family members.

Keywords

deacetylase; evolution; molecular phylogeny; SIR2; sirtuin;

Citations & Related Records

Times Cited By Web Of Science : 14 (Related Records In Web of Science)

Reference

1	Aparicio, O.M., Billington, B.L., and Gottschling, D.E. (1991). Modifiers of position effect are shared between telomeric and silent mating-type loci in S. cerevisiae. Cell 66, 1279-1287 DOI ScienceOn
2	Avalos, J.L., Celic, I., Muhammad, S., Cosgrove, M.S., Boeke, J.D., and Wolberger, C. (2002). Structure of a Sir2 enzyme bound to an acetylated p53 peptide. Mol. Cell 10, 523-535 DOI ScienceOn
3	Blander, G., Olejnik, J., Krzymanska-Olejnik, E., McDonagh, T., Haigis, M., Yaffe, M.B., and Guarente, L. (2005). SIRT1 shows no substrate specificity in vitro. J. Biol. Chem. 280, 9780-9785 DOI ScienceOn
4	Braunstein, M., Rose, A.B., Holmes, S.G., Allis, C.D., and Broach, J.R. (1993). Transcriptional silencing in yeast is associated with reduced nucleosome acetylation. Genes Dev. 7, 592-604 DOI ScienceOn
5	Dali-Youcef, N., Lagouge, M., Froelich, S., Koehl, C., Schoonjans, K., and Auwerx, J. (2007). Sirtuins: the 'magnificent seven', function, metabolism and longevity. Ann. Med. 39, 335-345 DOI ScienceOn
6	Du, J., Jiang, H., and Lin, H. (2009). Investigating the ADPribosyltransferase activity of sirtuins with NAD analogs and $^{32}P$ -NAD. Biochemistry 48, 2878-2890 DOI ScienceOn
7	Dryden, S.C., Nahhas, F.A., Nowak, J.E., Goustin, A.S., and Tainsky, M.A. (2003). Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle. Mol. Cell Biol. 23, 3173-3185 DOI ScienceOn
8	Fritze, C.E., Verschueren, K., Strich, R., and Easton, E.R. (1997). Direct evidence for SIR2 modulation of chromatin structure in yeast rDNA. EMBO J. 16, 6495-6509 DOI ScienceOn
9	Frye, R.A. (2000). Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem. Biophys. Res. Commun. 273, 793-798 DOI PUBMED ScienceOn
10	Gardner, M.J., Hall, N., Fung, E., White, O., Berriman, M., Hyman, R.W., Carlton, J.M., Pain, A., Nelson, K.E., Bowman, S., et al. (2002). Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419, 498-511 DOI ScienceOn
11	Holbert, M.A., and Marmorstein, R. (2005). Structure and activity of enzymes that remove histone modifications. Curr. Opin. Struct. Biol. 15, 673-680 DOI ScienceOn
12	Inoue, T., Hiratsuka, M., Osaki, M., Yamada, H., Kishimoto, I., Yamaguchi, S., Nakano, S., Katoh, M., Ito, H., and Oshimura, M. (2006). SIRT2, a tubulin deacetylase, acts to block the entry to chromosome condensation in response to mitotic stress. Oncogene 26, 945-957 DOI ScienceOn
13	Ivy, J.M., Hicks, J.B., and Klar, A.J. (1985). Map positions of yeast genes SIR1, SIR3 and SIR4. Genetics 111, 735-744 PUBMED
14	Kaeberlein, M., McVey, M., and Guarente, L. (1999). The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev. 13, 2570-2580 DOI ScienceOn
15	King, N., Westbrook, M.J., Young, S.L., Kuo, A., Abedin, M., Chapman, J., Fairclough, S., Hellsten, U., Isogai, Y., Letunic, I., et al. (2008). The genome of the choanoflagellate Monosiga brevicollis and the origin of metazoans. Nature 451, 783-788 DOI ScienceOn
16	Kowieski, T.M., Lee, S., and Denu, J.M. (2008). Acetylationdependent ADP-ribosylation by Trypanosoma brucei Sir2. J. Biol. Chem. 283, 5317-5326 DOI ScienceOn
17	Meng, E.C., Pettersen, E.F., Couch, G.S., Huang, C.C., and Ferrin, T.E. (2006). Tools for integrated sequence-structure analysis with UCSF Chimera. BMC Bioinformatics 7, 339 DOI PUBMED
18	Richards, S., Gibbs, R.A., Weinstock, G.M., Brown, S.J., Denell, R., Beeman, R.W., Gibbs, R., Bucher, G., Friedrich, M., Grimmelikhuijzen, C.J., et al. (2008). The genome of the model beetle and pest Tribolium castaneum. Nature 452, 949-955 DOI ScienceOn
19	Min, J., Landry, J., Sternglanz, R., and Xu, R.M. (2001). Crystal structure of a SIR2 homolog-NAD complex. Cell 105, 269-279 DOI ScienceOn
20	Rensing, S.A., Lang, D., Zimmer, A.D., Terry, A., Salamov, A., Shapiro, H., Nishiyama, T., Perroud, P.F., Lindquist, E.A., Kamisugi, Y., et al. (2008). The Physcomitrella genome reveals evolutionary insights into the conquest of land by plants. Science 319, 64-69 DOI PUBMED ScienceOn
21	Sauve, A.A., Celic, I., Avalos, J., Deng, H., Boeke, J.D., and Schramm, V.L. (2001). Chemistry of gene silencing: the mechanism of NAD+-dependent deacetylation reactions. Biochemistry 40, 15456-15463 DOI ScienceOn
22	Schlicker, C., Gertz, M., Papatheodorou, P., Kachholz, B., Becker, C.F., and Steegborn, C. (2008). Substrates and regulation mechanisms for the human mitochondrial sirtuins Sirt3 and Sirt5. J. Mol. Biol. 382, 790-801 DOI ScienceOn
23	Schwer, B., Bunkenborg, J., Verdin, R.O., Andersen, J.S., and Verdin, E. (2006). Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2. Proc. Natl. Acad. Sci. USA 103, 10224-10229 DOI ScienceOn
24	Shou, W., Seol, J.H., Shevchenko, A., Baskerville, C., Moazed, D., Chen, Z.W., Jang, J., Shevchenko, A., Charbonneau, H., and Deshaies, R.J. (1999). Exit from mitosis is triggered by Tem1- dependent release of the protein phosphatase Cdc14 from nucleolar RENT complex. Cell 97, 233-244 DOI ScienceOn
25	Tanno, M., Sakamoto, J., Miura, T., Shimamoto, K., and Horio, Y. (2007). Nucleocytoplasmic shuttling of the NAD+-dependent histone deacetylase SIRT1. J. Biol. Chem. 282, 6823-6832 DOI ScienceOn
26	Sinclair, D.A., and Guarente, L. (1997). Extrachromosomal rDNA circles - a cause of aging in yeast. Cell 91, 1033-1042 DOI ScienceOn
27	Smith, J.S., Brachmann, C.B., Celic, I., Kenna, M.A., Muhammad, S., Starai, V.J., Avalos, J.L., Escalante-Semerena, J.C., Grubmeyer, C., Wolberger, C., et al. (2000). A phylogenetically conserved NAD+-dependent protein deacetylase activity in the Sir2 protein family. Proc. Natl. Acad. Sci USA 97, 6658-6663 DOI ScienceOn
28	Srivastava, M., Begovic, E., Chapman, J., Putnam, N.H., Hellsten, U., Kawashima, T., Kuo, A., Mitros, T., Salamov, A., Carpenter, M.L., et al. (2008). The Trichoplax genome and the nature of placozoans. Nature 454, 955-960 DOI ScienceOn
29	Vaquero, A., Scher, M., Lee, D., Erdjument-Bromage, H., Tempst, P., and Reinberg, D. (2004). Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. Mol. Cell 16, 93-105 DOI ScienceOn
30	Zhao, K., Harshaw, R., Chai, X., and Marmorstein, R. (2004). Structural basis for nicotinamide cleavage and ADP-ribose transfer by NAD+-dependent Sir2 histone/protein deacetylases. Proc. Natl. Acad. Sci. USA 101, 8563-8568 DOI ScienceOn
31	Michishita, E., Park, J.Y., Burneskis, J.M., Barrett, J.C., and Horikawa, I. (2005). Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins. Mol. Biol. Cell 16, 4623-4635
32	Hallows, W.C., Lee, S., and Denu, J.M. (2006). Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases. Proc. Natl. Acad. Sci. USA 103, 10230-10235 DOI ScienceOn
33	Solignac, M., Zhang, L., Mougel, F., Li, B., Vautrin, D., Monnerot, M., Cornuet, J.M., Worley, K.C., Weinstock, G.M., and Gibbs, R.A. (2007). The genome of Apis mellifera: dialog between linkage mapping and sequence assembly. Genome Biol. 8, 403 DOI PUBMED
34	Straight, A.F., Shou, W., Dowd, G.J., Turck, C.W., Deshaies, R.J., Johnson, A.D., and Moazed, D. (1999). Net1, a Sir2-associated nucleolar protein required for rDNA silencing and nucleolar integrity. Cell 97, 245-256 DOI ScienceOn
35	Tsang, A.W., and Escalante-Semerena, J.C. (1998). CobB, a new member of the SIR2 family of eucaryotic regulatory proteins, is required to compensate for the lack of nicotinate mononucleotide: 5,6-dimethylbenzimidazole phosphoribosyltransferase activity in cobT mutants during cobalamin biosynthesis in Salmonella typhimurium LT2. J. Biol. Chem. 273, 31788-31794 DOI ScienceOn
36	Ford, E., Voit, R., Liszt, G., Magin, C., Grummt, I., and Guarente, L. (2006). Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcription. Genes Dev. 20, 1075-1080 DOI ScienceOn
37	Khan, A.N., and Lewis, P.N. (2005). Unstructured conformations are a substrate requirement for the Sir2 family of NADdependent protein deacetylases. J. Biol. Chem. 280, 36073-36078 DOI ScienceOn
38	Zhao, K., Chai, X., and Marmorstein, R. (2003b). Structure of the yeast Hst2 protein deacetylase in ternary complex with 2′-Oacetyl ADP ribose and histone peptide. Structure 11, 1403-1411 DOI ScienceOn
39	Huson, D.H., and Bryant, D. (2006). Application of phylogenetic networks in evolutionary studies. Mol. Biol. Evol. 23, 254-267 DOI ScienceOn
40	Ivy, J.M., Klar, A.J., and Hicks, J.B. (1986). Cloning and characterization of four SIR genes of Saccharomyces cerevisiae. Mol. Cell. Biol. 6, 688-702 DOI PUBMED
41	Picard, F., Kurtev, M., Chung, N., Topark-Ngarm, A., Senawong, T., Machado, D.O., Leid, M., McBurney, M.W., and Guarente, L. (2004). Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 429, 771-776 DOI PUBMED ScienceOn
42	Yamamoto, H., Schoonjans, K., and Auwerx, J. (2007). Sirtuin functions in health and disease. Mol. Endocrinol. 21, 1745-1755 DOI ScienceOn
43	Lombard, D.B., Schwer, B., Alt, F.W., and Mostoslavsky, R. (2008). SIRT6 in DNA repair, metabolism and ageing. J. Intern. Med. 263, 128-141 DOI PUBMED ScienceOn
44	Baldauf, S.L. (2003). The deep roots of eukaryotes. Science 300, 1703-1706 DOI PUBMED ScienceOn
45	Vaquero, A., Scher, M., Erdjument-Bromage, H., Tempst, P., Serrano, L., and Reinberg, D. (2007). SIRT1 regulates the histone methyltransferase SUV39H1 during heterochromatin formation. Nature 450, 440-444 DOI ScienceOn
46	Ahuja, N., Schwer, B., Carobbio, S., Waltregny, D., North, B.J., Castronovo, V., Maechler, P., and Verdin, E. (2007). Regulation of insulin secretion by SIRT4, a mitochondrial ADP-ribosyltransferase. J. Biol. Chem. 282, 33583-33592 DOI ScienceOn
47	Finnin, M.S., Donigian, J.R., and Pavletich, N.P. (2001). Structure of the histone deacetylase SIRT2. Nat. Struct. Biol. 8, 621-625 DOI ScienceOn
48	Hiratsuka, M., Inoue, T., Toda, T., Kimura, N., Shirayoshi, Y., Kamitani, H., Watanabe, T., Ohama, E., Tahimic, C.G., Kurimasa, A., et al. (2003). Proteomics-based identification of differentially expressed genes in human gliomas: down-regulation of SIRT2 gene. Biochem. Biophys. Res. Commun. 309, 558-566 DOI ScienceOn
49	Potente, M., Ghaeni, L., Baldessari, D., Mostoslavsky, R., Rossig, L., Dequiedt, F., Haendeler, J., Mione, M., Dejana, E., Alt, F.W., et al. (2007). SIRT1 controls endothelial angiogenic functions during vascular growth. Genes Dev. 21, 2644-2658 DOI ScienceOn
50	Stein, L.D., Bao, Z., Blasiar, D., Blumenthal, T., Brent, M.R., Chen, N., Chinwalla, A., Clarke, L., Clee, C., Coghlan, A., et al. (2003). The genome sequence of Caenorhabditis briggsae: a platform for comparative genomics. PLoS Biol. 1, E45 DOI PUBMED
51	Longo, V.D., and Kennedy, B.K. (2006). Sirtuins in aging and agerelated disease. Cell 126, 257-268 DOI ScienceOn
52	Pettersen, E.F., Goddard, T.D., Huang, C.C., Couch, G.S., Greenblatt, D.M., Meng, E.C., and Ferrin, T.E. (2004). UCSF Chimera - a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605-1612 DOI ScienceOn
53	van der Horst, A., Tertoolen, L.G., Vries-Smits, L.M., Frye, R.A., Medema, R.H., and Burgering, B.M. (2004). FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2SIRT1. J. Biol. Chem. 279, 28873-28879 DOI ScienceOn
54	Eichinger, L., Pachebat, J.A., Glockner, G., Rajandream, M.A., Sucgang, R., Berriman, M., Song, J., Olsen, R., Szafranski, K., Xu, Q., et al. (2005). The genome of the social amoeba Dictyostelium discoideum. Nature 435, 43-57 DOI ScienceOn
55	Tanny, J.C., Dowd, G.J., Huang, J., Hilz, H., and Moazed, D. (1999). An enzymatic activity in the yeast Sir2 protein that is essential for gene silencing. Cell 99, 735-745 DOI ScienceOn
56	Mead, J., McCord, R., Youngster, L., Sharma, M., Gartenberg, M.R., and Vershon, A.K. (2007). Swapping the gene-specific and regional silencing specificities of the Hst1 and Sir2 histone deacetylases. Mol. Cell. Biol. 27, 2466-2475 DOI ScienceOn
57	Oberdoerffer, P., Michan, S., McVay, M., Mostoslavsky, R., Vann, J., Park, S.K., Hartlerode, A., Stegmuller, J., Hafner, A., Loerch, P., et al. (2008). SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 135, 907-918 DOI ScienceOn
58	Rosenberg, M.I., and Parkhurst, S.M. (2002). Drosophila Sir2 is required for heterochromatic silencing and by euchromatic Hairy/E(Spl). bHLH repressors in segmentation and sex determination. Cell 109, 447-458 DOI ScienceOn
59	Wang, C., Chen, L., Hou, X., Li, Z., Kabra, N., Ma, Y., Nemoto, S., Finkel, T., Gu, W., Cress, W.D., et al. (2006). Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage. Nat. Cell Biol. 8, 1025-1031 DOI ScienceOn
60	Tanny, J.C., and Moazed, D. (2001). Coupling of histone deacetylation to NAD breakdown by the yeast silencing protein Sir2: Evidence for acetyl transfer from substrate to an NAD breakdown product. Proc. Natl. Acad. Sci. USA 98, 415-420 DOI ScienceOn
61	Bowler, C., Allen, A.E., Badger, J.H., Grimwood, J., Jabbari, K., Kuo, A., Maheswari, U., Martens, C., Maumus, F., Otillar, R.P., et al. (2008). The Phaeodactylum genome reveals the evolutionary history of diatom genomes. Nature 456, 239-244 DOI ScienceOn
62	Vaquero, A., Scher, M.B., Lee, D.H., Sutton, A., Cheng, H.L., Alt, F.W., Serrano, L., Sternglanz, R., and Reinberg, D. (2006). SirT2 is a histone deacetylase with preference for histone H4 Lys 16 during mitosis. Genes Dev. 20, 1256-1261 DOI ScienceOn
63	Zhao, K., Chai, X., Clements, A., and Marmorstein, R. (2003a). Structure and autoregulation of the yeast Hst2 homolog of Sir2. Nat. Struct. Biol. 10, 864-871 DOI ScienceOn
64	Brunet, A., Sweeney, L.B., Sturgill, J.F., Chua, K.F., Greer, P.L., Lin, Y., Tran, H., Ross, S.E., Mostoslavsky, R., Cohen, H.Y., et al. (2004). Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303, 2011-2015 DOI PUBMED ScienceOn
65	Dai, J.M., Wang, Z.Y., Sun, D.C., Lin, R.X., and Wang, S.Q. (2007). SIRT1 interacts with p73 and suppresses p73-dependent transcriptional activity. J. Cell Physiol. 210, 161-166 DOI ScienceOn
66	Gottlieb, S., and Esposito, R.E. (1989). A new role for a yeast transcriptional silencer gene, SIR2, in regulation of recombination in ribosomal DNA. Cell 56, 771-776 DOI ScienceOn
67	Landry, J., Sutton, A., Tafrov, S.T., Heller, R.C., Stebbins, J., Pillus, L., and Sternglanz, R. (2000). The silencing protein SIR2 and its homologs are NAD dependent protein deacetylases. Proc. Natl. Acad. Sci. USA 97, 5807-5811 DOI ScienceOn
68	Tanner, K.G., Landry, J., Sternglanz, R., and Denu, J.M. (2000). Silent information regulator 2 family of NAD- dependent histone/ protein deacetylases generates a unique product, 1-Oacetyl- ADP-ribose. Proc. Natl. Acad. Sci. USA 97, 14178-14182 DOI ScienceOn
69	Vaziri, H., Dessain, S.K., Ng, E.E., Imai, S.I., Frye, R.A., Pandita, T.K., Guarente, L., and Weinberg, R.A. (2001). hSIR2(SIRT1). functions as an NAD-dependent p53 deacetylase. Cell 107, 149-159 DOI ScienceOn
70	Wood, J.G., Rogina, B., Lavu, S., Howitz, K., Helfand, S.L., Tatar, M., and Sinclair, D. (2004). Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 430, 686-689 DOI ScienceOn
71	Der Ou, H.D., Lohr, F., Vogel, V., Mantele, W., and Dotsch, V. (2007). Structural evolution of C-terminal domains in the p53 family. EMBO J. 26, 3463-3473 DOI PUBMED ScienceOn
72	Pruitt, K., Zinn, R.L., Ohm, J.E., McGarvey, K.M., Kang, S.H., Watkins, D.N., Herman, J.G., and Baylin, S.B. (2006). Inhibition of SIRT1 reactivates silenced cancer genes without loss of promoter DNA hypermethylation. PLoS Genet. 2, e40 DOI PUBMED
73	Katinka, M.D., Duprat, S., Cornillot, E., Metenier, G., Thomarat, F., Prensier, G., Barbe, V., Peyretaillade, E., Brottier, P., Wincker, P., et al. (2001). Genome sequence and gene compaction of the eukaryote parasite Encephalitozoon cuniculi. Nature 414, 450-453 DOI ScienceOn
74	Liszt, G., Ford, E., Kurtev, M., and Guarente, L. (2005). Mouse Sir2 homolog SIRT6 is a nuclear ADP-ribosyltransferase. J. Biol. Chem. 280, 21313-21320 DOI ScienceOn
75	Waterhouse, A.M., Procter, J.B., Martin, D.M., Clamp, M., and Barton, G.J. (2009). Jalview Version 2 - a multiple sequence alignment editor and analysis workbench. Bioinformatics 25, 1189-1191 DOI ScienceOn
76	Imai, S., Armstrong, C.M., Kaeberlein, M., and Guarente, L. (2000). Transcriptional silencing and longevity protein Sir2 is an NADdependent histone deacetylase. Nature 403, 795-800 DOI ScienceOn
77	Astrom, S.U., Cline, T.W., and Rine, J. (2003). The Drosophila melanogaster sir2+ gene is nonessential and has only minor effects on position-effect variegation. Genetics 163, 931-937 PUBMED
78	Tissenbaum, H.A., and Guarente, L. (2001). Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans. Nature 410, 227-230 DOI ScienceOn
79	Ghedin, E., Wang, S., Spiro, D., Caler, E., Zhao, Q., Crabtree, J., Allen, J.E., Delcher, A.L., Guiliano, D.B., Miranda-Saavedra, D., et al. (2007). Draft genome of the filarial nematode parasite Brugia malayi. Science 317, 1756-1760 DOI PUBMED ScienceOn
80	Haigis, M.C., and Guarente, L.P. (2006). Mammalian sirtuins - emerging roles in physiology, aging, and calorie restriction. Genes Dev. 20, 2913-2921 DOI ScienceOn
81	Newman, B.L., Lundblad, J.R., Chen, Y., and Smolik, S.M. (2002). A Drosophila homologue of Sir2 modifies position-effect variegation but does not affect life span. Genetics 162, 1675-1685 PUBMED
82	Braunstein, M., Sobel, R.E., Allis, C.D., Turner, B.M., and Broach, J.R. (1996). Efficient transcriptional silencing in Saccharomyces cerevisiae requires a heterochromatin histone acetylation pattern. Mol. Cell Biol. 16, 4349-4356 DOI PUBMED
83	Bryk, M., Banerjee, M., Murphy, M., Knudsen, K.E., Garfinkel, D.J., and Curcio, M.J. (1997). Transcriptional silencing of Ty1 elements in the RDN1 locus of yeast. Genes Dev. 11, 255-269 DOI ScienceOn
84	Chang, J.H., Kim, H.C., Hwang, K.Y., Lee, J.W., Jackson, S.P., Bell, S.D., and Cho, Y. (2002). Structural basis for the NAD-dependent deacetylase mechanism of Sir2. J. Biol. Chem. 277, 34489-34498 DOI ScienceOn
85	Greiss, S., Hall, J., Ahmed, S., and Gartner, A. (2008). C. elegans SIR-2.1 translocation is linked to a proapoptotic pathway parallel to cep-1/p53 during DNA damage-induced apoptosis. Genes Dev. 22, 2831-2842 DOI ScienceOn
86	Haigis, M.C., Mostoslavsky, R., Haigis, K.M., Fahie, K., Christodoulou, D.C., Murphy, A.J., Valenzuela, D.M., Yancopoulos, G.D., Karow, M., Blander, G., et al. (2006). SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. Cell 126, 941-954 DOI PUBMED ScienceOn
87	Yeung, F., Hoberg, J.E., Ramsey, C.S., Keller, M.D., Jones, D.R., Frye, R.A., and Mayo, M.W. (2004). Modulation of NF-kappaBdependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 23, 2369-2380 DOI PUBMED ScienceOn
88	Luo, J., Nikolaev, A.Y., Imai, S., Chen, D., Su, F., Shiloh, A., Guarente, L., and Gu, W. (2001). Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell 107, 137-148 DOI PUBMED ScienceOn
89	Cohen, H.Y., Miller, C., Bitterman, K.J., Wall, N.R., Hekking, B., Kessler, B., Howitz, K.T., Gorospe, M., de Cabo, R., and Sinclair, D.A. (2004). Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305, 390-392 DOI PUBMED ScienceOn
90	Hu, P., Wang, S., and Zhang, Y. (2008). Highly dissociative and concerted mechanism for the nicotinamide cleavage reaction in Sir2Tm enzyme suggested by Ab Initio QM/MM molecular dynamics simulations. J. Am. Chem. Soc. 130, 16721-16728 DOI ScienceOn
91	Motta, M.C., Divecha, N., Lemieux, M., Kamel, C., Chen, D., Gu, W., Bultsma, Y., McBurney, M., and Guarente, L. (2004). Mammalian SIRT1 represses forkhead transcription factors. Cell 116, 551-563 DOI ScienceOn
92	Rodgers, J.T., Lerin, C., Haas, W., Gygi, S.P., Spiegelman, B.M., and Puigserver, P. (2005). Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 434, 113-118 DOI PUBMED ScienceOn
93	North, B.J., and Verdin, E. (2004). Sirtuins: Sir2-related NADdependent protein deacetylases. Genome Biol. 5, 224 DOI PUBMED
94	Jin, Q., Yan, T., Ge, X., Sun, C., Shi, X., and Zhai, Q. (2007). Cytoplasm- localized SIRT1 enhances apoptosis. J. Cell Physiol. 213, 88-97 DOI ScienceOn
95	Klar, A.J., Fogel, S., and Macleod, K. (1979). MAR1 - a Regulator of the HMa and HMα Loci in Saccharomyces cerevisiae. Genetics 93, 37-50 PUBMED
96	Pankow, S., and Bamberger, C. (2007). The p53 tumor suppressorlike protein nvp63 mediates selective germ cell death in the sea anemone Nematostella vectensis. PLoS ONE 2, e782 DOI PUBMED
97	Kawahara, T.L., Michishita, E., Adler, A.S., Damian, M., Berber, E., Lin, M., McCord, R.A., Ongaigui, K.C., Boxer, L.D., Chang, H.Y., et al. (2009). SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span. Cell 136, 62-74 DOI PUBMED ScienceOn
98	Rogina, B., and Helfand, S.L. (2004). Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc. Natl. Acad. Sci. USA 101, 15998-16003 DOI ScienceOn
99	Michishita, E., McCord, R.A., Berber, E., Kioi, M., Padilla-Nash, H., Damian, M., Cheung, P., Kusumoto, R., Kawahara, T.L., Barrett, J.C., et al. (2008). SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Nature 452, 492-496 DOI ScienceOn
100	Schwer, B., and Verdin, E. (2008). Conserved metabolic regulatory functions of sirtuins. Cell Metab. 7, 104-112 DOI ScienceOn

Reference

9	(2010) PLoS genetics Synthesizing and Salvaging NAD <SUP>+</SUP> : Lessons Learned from <I>Chlamydomonas reinhardtii</I> / 6 (9) , e1001105
3	(2009) MedChemComm Discovery of potent, proteolytically stable, and cell permeable human sirtuin peptidomimetic inhibitors containing N<SUP>ϵ</SUP>-thioacetyl-lysine / 1 (3) , 233
4	(2009) MedChemComm Potent sirtuin inhibition bestowed by <SMALL>L</SMALL>-2-amino-7-carboxamidoheptanoic acid (<SMALL>L</SMALL>-ACAH), a N<SUP>ε</SUP>-acetyl-lysine analog / 2 (4) , 291
16	(2009) Molecular and cellular biology The Duplicated Deacetylases Sir2 and Hst1 Subfunctionalized by Acquiring Complementary Inactivating Mutations / 31 (16) , 3351
5	(2009) Human genomics The human sirtuin family: Evolutionary divergences and functions / 5 (5) , 485
4	(2009) Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism Pathways for Ischemic Cytoprotection: Role of Sirtuins in Caloric Restriction, Resveratrol, and Ischemic Preconditioning / 31 (4) , 1003
2	(2009) Cellular and molecular life sciences : CMLS Functions of the poly(ADP-ribose) polymerase superfamily in plants / 69 (2) , 175
3	(2009) Physiological reviews Sirtuin 1 and Sirtuin 3: Physiological Modulators of Metabolism / 92 (3) , 1479
2	(2009) Molecular and biochemical parasitology Sirtuins of parasitic protozoa: In search of function(s) / 185 (2) , 71
10	(2009) PLoS genetics The Deacetylase Sir2 from the Yeast <I>Clavispora lusitaniae</I> Lacks the Evolutionarily Conserved Capacity to Generate Subtelomeric Heterochromatin / 9 (10) , e1003935
9	(2009) PLoS neglected tropical diseases <I>Schistosoma mansoni</I> Sirtuins: Characterization and Potential as Chemotherapeutic Targets / 7 (9) , e2428
6	(2009) PLoS ONE The Rice NAD <SUP>+</SUP> -Dependent Histone Deacetylase OsSRT1 Targets Preferentially to Stress- and Metabolism-Related Genes and Transposable Elements / 8 (6) , e66807
None	(2009) Annual review of genetics SIR Proteins and the Assembly of Silent Chromatin in Budding Yeast / 47 (None) , 275
6	(2009) Biogerontology SIRT6, a protein with many faces / 14 (6) , 629
12	(2009) Protein science : a publication of the Protein Society Alternate deacylating specificities of the archaeal sirtuins Sir2Af1 and Sir2Af2 / 23 (12) , 1686
7	(2014) PLoS genetics Silencing Is Noisy: Population and Cell Level Noise in Telomere-Adjacent Genes Is Dependent on Telomere Position and Sir2 / 10 (7) , e1004436
None	(2009) Frontiers in genetics Epigenetic control of gene function in schistosomes: a source of therapeutic targets? / 5 (None) , 317
None	(2009) Frontiers in aging neuroscience Differential expression of sirtuin family members in the developing, adult, and aged rat brain / 6 (None) , 333
2	(2009) Worm C. elegans sirtuin SIR-2.4 and its mammalian homolog SIRT6 in stress response. / 3 (2) , 29102
4	(2009) PLoS ONE Structural, Kinetic and Proteomic Characterization of Acetyl Phosphate-Dependent Bacterial Protein Acetylation / 9 (4) , e94816
5	(2014) Advances in nutrition : an international review journal Polyphenols and the Human Brain: Plant “Secondary Metabolite” Ecologic Roles and Endogenous Signaling Functions Drive Benefits / 5 (5) , 515
None	Nehmé Saksouk. (2009) Epigenetics & chromatin Constitutive heterochromatin formation and transcription in mammals / 8 (None) , 3
None	(2009) Frontiers in cell and developmental biology SIRT7 and hepatic lipid metabolism / 3 (None) , 1
6	(2009) Future medicinal chemistry Schistosome sirtuins as drug targets / 7 (6) , 765
1	(2009) Journal of biomolecular screening : the official journal of the Society for Biomolecular Screening Fluorescence-Based Screening Assays for the NAD<SUP>+</SUP>-Dependent Histone Deacetylase smSirt2 from <I>Schistosoma mansoni</I> / 20 (1) , 112
2	(2015) International journal of molecular sciences Expression of the SIRT2 Gene and Its Relationship with Body Size Traits in Qinchuan Cattle ( <I>Bos taurus</I> ) / 16 (2) , 2458
4	(2009) PLoS neglected tropical diseases Overexpression of Cytoplasmic <I>Tc</I> SIR2RP1 and Mitochondrial <I>Tc</I> SIR2RP3 Impacts on <I>Trypanosoma cruzi</I> Growth and Cell Invasion / 9 (4) , e0003725
3	(2009) Microbiology spectrum Glycolysis for Microbiome Generation / 3 (3) , None
2	(2009) Molecular cell Identification of a Class of Protein ADP-Ribosylating Sirtuins in Microbial Pathogens / 59 (2) , 309
6	(2009) FEMS yeast research Local and regional chromatin silencing in<I>Candida glabrata</I>: consequences for adhesion and the response to stress / 15 (6) , fov056
12	(2009) Circulation Sirt7 Contributes to Myocardial Tissue Repair by Maintaining Transforming Growth Factor-β Signaling Pathway / 132 (12) , 1081
3	(2009) Journal of physiology and biochemistry The role of sirtuins in cellular homeostasis / 72 (3) , 371
4	(2009) Epigenetics : official journal of the DNA Methylation Society <I>Anaplasma phagocytophilum</I>increases the levels of histone modifying enzymes to inhibit cell apoptosis and facilitate pathogen infection in the tick vector<I>Ixodes scapularis</I> / 11 (4) , 303
None	(2009) Frontiers in cellular and infection microbiology Epigenetics in Schistosomes: What We Know and What We Need Know / 6 (None) , 149
None	(2009) Scientific reports <I>Candida albicans</I> repetitive elements display epigenetic diversity and plasticity / 6 (None) , 22989
25	(2009) Organic & biomolecular chemistry Cyclic peptide-based potent human SIRT6 inhibitors / 14 (25) , 5928
9	(2009) Molecules A Selective Cyclic Peptidic Human SIRT5 Inhibitor / 21 (9) , 1217
1	(2009) Journal of comparative physiology. B, Biochemical, systemic, and environmental physiology Tissue-specific gene expression and fasting regulation of sirtuin family in gilthead sea bream (Sparus aurata) / 187 (1) , 153
10	(2009) G3 : genes - genomes - genetics Sporadic Gene Loss After Duplication Is Associated with Functional Divergence of Sirtuin Deacetylases Among <I>Candida</I> Yeast Species / 6 (10) , 3297
21	(2009) Bioorganic & medicinal chemistry letters Cyclic peptide-based potent and selective SIRT½ dual inhibitors harboring N<SUP>&epsi;</SUP>-thioacetyl-lysine / 26 (21) , 5234
6	(2017) Cell stress & chaperones Thermal treatment of luteolin-7-O-β-glucoside improves its immunomodulatory and antioxidant potencies / 22 (6) , 775
None	(2009) Frontiers in microbiology Modulation of Replicative Lifespan in <I>Cryptococcus neoformans</I> : Implications for Virulence / 8 (None) , 98
1	(2017) Journal of the indian institute of science Spatio-Temporal Control of Cellular and Organismal Physiology by Sirtuins / 97 (1) , 147
4	(2009) Cell metabolism SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion / 25 (4) , 838
8	(2017) PLoS ONE Molecular evolutionary patterns of NAD <SUP>+</SUP> /Sirtuin aging signaling pathway across taxa / 12 (8) , e0182306
None	(2017) Scientific reports Alkylresorcinols activate SIRT1 and delay ageing in <I>Drosophila melanogaster</I> / 7 (None) , 43679
None	(2009) Scientific reports Sirtuins in the phylum Basidiomycota: A role in virulence in <I>Cryptococcus neoformans</I> / 7 (None) , 46567
26	(2009) Biochemistry An NAD<SUP>+</SUP>-Dependent Sirtuin Depropionylase and Deacetylase (Sir2La) from the Probiotic Bacterium <I>Lactobacillus acidophilus</I> NCFM / 57 (26) , 3903
8	(2009) Antioxidants & redox signaling The Role of Sirtuins in Antioxidant and Redox Signaling / 28 (8) , 643
11	(2009) The FASEB journal : official publication of the Federation of American Societies for Experimental Biology SIRT7 functions in redox homeostasis and cytoskeletal organization during oocyte maturation / 32 (11) , 6228
None	(2009) Frontiers in physiology Co-expression Analysis of Sirtuins and Related Metabolic Biomarkers in Juveniles of Gilthead Sea Bream ( <I>Sparus aurata</I> ) With Differences in Growth Performance / 9 (None) , 608
1	(2018) Journal of fungi Differences in Sirtuin Regulation in Response to Calorie Restriction in <I>Cryptococcus neoformans</I> / 4 (1) , 26
7	(2018) Proceedings of the National Academy of Sciences of the United States of America Sirt4 is a mitochondrial regulator of metabolism and lifespan in <I>Drosophila melanogaster</I> / 115 (7) , 1564
4	(2009) Critical reviews in plant sciences NAD<SUP>+</SUP>Biosynthesis and Signaling in Plants / 37 (4) , 259
11	(2009) International journal of molecular sciences Hsp90 Stabilizes SIRT1 Orthologs in Mammalian Cells and <I>C. elegans</I> / 19 (11) , 3661
None	(2018) Scientific reports Directed evolution of SIRT6 for improved deacylation and glucose homeostasis maintenance / 8 (None) , 3538
12	(2009) EMBO reports Arginine methylation of <SMALL>SIRT</SMALL> 7 couples glucose sensing with mitochondria biogenesis / 19 (12) , None
18	(2009) Critical reviews in food science and nutrition Nutritional biomarkers: Current view and future perspectives / 58 (18) , 3055
None	(2009) Frontiers in genetics Genetic Pathways of Aging and Their Relevance in the Dog as a Natural Model of Human Aging / 10 (None) , 948
3	(2009) Molecules Cyclic Peptide-Based Sirtuin Substrates / 24 (3) , 424
4	(2009) ChemMedChem : Chemistry Enabling Drug Discovery Unpacking the Pathogen Box-An Open Source Tool for Fighting Neglected Tropical Disease / 14 (4) , 386
3	(2009) Genome biology and evolution Evolution of the <I>Drosophila melanogaster</I> Chromatin Landscape and Its Associated Proteins / 11 (3) , 660
18	(2019) The EMBO journal Interplay between the bacterial protein deacetylase CobB and the second messenger c‐di‐ <SMALL>GMP</SMALL> / 38 (18) , None
3	(2009) Medicinal chemistry Cyclic Tripeptide-based Potent and Selective Human SIRT5 Inhibitors / 16 (3) , 358
1	(2009) Nature communications Structural and functional evidence of bacterial antiphage protection by Thoeris defense system via NAD <SUP>+</SUP> degradation / 11 (1) , 2816
None	(2020) Frontiers in cellular and infection microbiology <I>Legionella pneumophila</I> Infection Rewires the <I>Acanthamoeba castellanii</I> Transcriptome, Highlighting a Class of Sirtuin Genes / 10 (None) , 428
5	(2009) Mammalian genome : official journal of the International Mammalian Genome Society Epigenetics and genome stability / 31 (5) , 181
None	(2020) Frontiers in cell and developmental biology The Versatility of Sirtuin-1 in Endocrinology and Immunology / 8 (None) , 589016
1	(2009) 생명과학회지 A Review of Sirtuin Inhibitors in Therapeutics, Pharmaceutics, and Plant Research / 30 (1) , 96
3	(2020) Archives of insect biochemistry and physiology Inhibition of histone acetylation and deacetylation enzymes affects longevity, development, and fecundity in the pea aphid (<I>Acyrthosiphon pisum</I>) / 103 (3) , e21614
None	(2009) Mechanisms of ageing and development SIRT1 Regulation in Ageing and Obesity / 188 (None) , 111249
15	(2009) ChemMedChem : Chemistry Enabling Drug Discovery Activation of Sirtuin 2 Inhibitors Employing Photoswitchable Geometry and Aqueous Solubility / 15 (15) , 1480
32	(2020) The Journal of biological chemistry Biological and catalytic functions of sirtuin 6 as targets for small-molecule modulators / 295 (32) , 11021
None	(2009) Frontiers in zoology Local DNA methylation helps to regulate muscle sirtuin 1 gene expression across seasons and advancing age in gilthead sea bream ( <I>Sparus aurata</I> ) / 17 (None) , 15
None	(2009) Postępy higieny i medycyny do&sacute;wiadczalnej Sirtuins: Enzymes with multidirectional catalytic activity / 75 (None) , 152
None	(2009) Frontiers in cardiovascular medicine Post-translational Acetylation Control of Cardiac Energy Metabolism / 8 (None) , 723996
None	(2009) Frontiers in microbiology Bacterial Sirtuins Overview: An Open Niche to Explore / 12 (None) , 744416
None	(2009) Frontiers in microbiology Post-translational Lysine Ac(et)ylation in Bacteria: A Biochemical, Structural, and Synthetic Biological Perspective / 12 (None) , 757179
2	(2021) Cells The Pleiotropic Function of Human Sirtuins as Modulators of Metabolic Pathways and Viral Infections / 10 (2) , 460
2	(2009) Molecular biology and evolution Human SIRT1 Multispecificity Is Modulated by Active-Site Vicinity Substitutions during Natural Evolution / 38 (2) , 545
3	(2009) Biology Sirtuins-Mediated System-Level Regulation of Mammalian Tissues at the Interface between Metabolism and Cell Cycle: A Systematic Review / 10 (3) , 194
11	(2009) International journal of molecular sciences The Mystery of Extramitochondrial Proteins Lysine Succinylation / 22 (11) , 6085
3	(2009) MSphere Genetic Analysis of Sirtuin Deacetylases in Hyphal Growth of <I>Candida albicans</I> / 6 (3) , None
None	(2021) Mitochondrion Energy Metabolism Focused Analysis of Sexual Dimorphism in Biological Aging and Hypothesized Sex-specificity in Sirtuin Dependency / 60 (None) , 85
9	(2009) Environmental microbiology A fungal sirtuin modulates development and virulence in the insect pathogen, <I>Beauveria bassiana</I> / 23 (9) , 5164
22	(2009) International journal of molecular sciences Sirtuins and Autophagy in Age-Associated Neurodegenerative Diseases: Lessons from the C. elegans Model / 22 (22) , 12263