The catalytic activity of sirtuins in physiology and
disease from the epigenetic point of view

• Authors: Diego Albani , Gianluigi Forloni
• Languages of publication: EN

Abstracts

EN

Sirtuins are a family of conserved enzymes that
are involved in physiological and pathological pathways
and have been investigated in relation to the ageing
process. There are seven different sirtuins in mammals
that are encoded by individual genes (SIRT1-7). Sirtuins
share a highly conserved catalytic domain, and they have
NAD+ dependent deacetylase activity and secondary ADPribosylase
activity in different proportions and on different
molecular targets. Sirtuins might be pharmacologically
modulated by small molecules that might represent a novel
class of “epigenetic” drugs. In fact, sirtuins’ deacetylase
activity may impact the epigenetic regulation network
acting on histones or affecting chromatin stability, while
the mono-ADP-ribosylase catalysis is less explored to this
respect. Here we review and discuss the potential impact
of sirtuin catalytic activities from the epigenetic pointof-
view, with a focus on age-related diseases (cancer,

Keywords

EN

Epigenetics; sirtuin; deacetylation; ADPribosylation; degenerative disorders)

• Publisher: De Gruyter Open
• Journal: Epigenetics of Degenerative Diseases
• Year: 2013
• Volume: 1
• Issue: 1

Dates

accepted

23 - 5 - 2014

received

4 - 4 - 2014

online

9 - 6 - 2014

Contributors

author

Diego Albani

• Department of Neuroscience,
  Mario Negri Institute for Pharmacological Research Via La Masa 19,
  20156 Milan, Italy, Phone: [phone], Fax: [phone],
  E-mail:
• Laboratory of Biology of Neurodegenerative
  Disorders, Department of Neuroscience IRCCS - Istituto di Ricerche Farmacologiche “Mario Negri”, via La
  Masa 19, 20156 Milan, Italy

author

Gianluigi Forloni

• Laboratory of Biology of Neurodegenerative
  Disorders, Department of Neuroscience IRCCS - Istituto di Ricerche Farmacologiche “Mario Negri”, via La
  Masa 19, 20156 Milan, Italy

References

• [1] North BJ, Verdin E. Sirtuins: Sir2-related NAD-dependentprotein deacetylases. Genome Biol 2004; 5: 224.[Crossref]
• [2] Frye RA. Phylogenetic classification of prokaryotic andeukaryotic Sir2-like proteins. Biochem Biophys Res Commun2000; 273: 793-798.
• [3] Yu J, Auwerx J. The role of sirtuins in the control of metabolichomeostasis. Ann N Y Acad Sci 2009; 1173 Suppl 1: E10-19.
• [4] Hall JA, Dominy JE, Lee Y, Puigserver P. The sirtuin family’s rolein aging and age-associated pathologies. J Clin Invest 2013;123: 973-979.
• [5] Song NY, Surh YJ. Janus-faced role of SIRT1 in tumorigenesis.Ann N Y Acad Sci 2012; 1271: 10-19.
• [6] Yuan J, Minter-Dykhouse K, Lou Z. A c-Myc-SIRT1 feedback loopregulates cell growth and transformation. J Cell Biol 2009; 185:203-211.
• [7] Schemies J, Sippl W, Jung M. Histone deacetylase inhibitorsthat target tubulin. Cancer Lett 2009; 280: 222-232.
• [8] Vaquero A, Sternglanz R, Reinberg D. NAD+-dependentdeacetylation of H4 lysine 16 by class III HDACs. Oncogene2007; 26: 5505-5520.[Crossref]
• [9] Wang F, Nguyen M, Qin FX, Tong Q. SIRT2 deacetylates FOXO3ain response to oxidative stress and caloric restriction. AgingCell 2007; 6: 505-514.[Crossref][PubMed]
• [10] Jing E, Gesta S, Kahn CR. SIRT2 regulates adipocyte differentiationthrough FoxO1 acetylation/deacetylation. Cell Metab2007; 6: 105-114.[Crossref]
• [11] Hallows WC, Lee S, Denu JM. Sirtuins deacetylate and activatemammalian acetyl-CoA synthetases. Proc Natl Acad Sci U S A2006; 103: 10230-10235.
• [12] Schlicker C, Gertz M, Papatheodorou P, Kachholz B, Becker CF,Steegborn C. Substrates and regulation mechanisms for thehuman mitochondrial sirtuins Sirt3 and Sirt5. J Mol Biol 2008;382: 790-801.
• [13] Shi T, Wang F, Stieren E, Tong Q. SIRT3, a mitochondrialsirtuin deacetylase, regulates mitochondrial function andthermogenesis in brown adipocytes. J Biol Chem 2005; 280:13560-13567.
• [14] Haigis MC, Mostoslavsky R, Haigis KM, Fahie K, ChristodoulouDC, Murphy AJ, et al. SIRT4 inhibits glutamate dehydrogenaseand opposes the effects of calorie restriction in pancreatic betacells. Cell 2006; 126: 941-954.
• [15] Ahuja N, Schwer B, Carobbio S, Waltregny D, North BJ,Castronovo V, et al. Regulation of insulin secretion by SIRT4, amitochondrial ADP-ribosyltransferase. J Biol Chem 2007; 282:33583-33592.
• [16] Nakagawa T, Guarente L. Urea cycle regulation by mitochondrialsirtuin, SIRT5. Aging (Albany NY) 2009; 1: 578-581.
• [17] Toiber D, Erdel F, Bouazoune K, Silberman DM, Zhong L,Mulligan P, et al. SIRT6 recruits SNF2H to DNA break sites,preventing genomic instability through chromatin remodeling.Mol Cell 2013; 51: 454-68.[Crossref]
• [18] Zhong L, D’Urso A, Toiber D, Sebastian C, Henry RE,Vadysirisack DD, et al. The histone deacetylase Sirt6 regulatesglucose homeostasis via Hif1alpha. Cell 140: 280-293.
• [19] Vakhrusheva O, Smolka C, Gajawada P, Kostin S, BoettgerT, Kubin T, et al. Sirt7 increases stress resistance of cardiomyocytesand prevents apoptosis and inflammatorycardiomyopathy in mice. Circ Res 2008; 102: 703-710.
• [20] Grob A, Roussel P, Wright JE, McStay B, Hernandez-VerdunD, Sirri V. Involvement of SIRT7 in resumption of rDNAtranscription at the exit from mitosis. J Cell Sci 2009; 122:489-498.
• [21] Sinclair DA, Guarente L. Extrachromosomal rDNA circles--acause of aging in yeast. Cell 1997; 91: 1033-1042.
• [22] Kaeberlein M, McVey M, Guarente L. The SIR2/3/4 complex andSIR2 alone promote longevity in Saccharomyces cerevisiae bytwo different mechanisms. Genes Dev 1999; 13: 2570-2580.[Crossref][PubMed]
• [23] Guarente L, Kenyon C. Genetic pathways that regulate ageingin model organisms. Nature 2000; 408: 255-262.
• [24] Burnett C, Valentini S, Cabreiro F, Goss M, Somogyvári M, PiperMD et al. Absence of effects of Sir2 overexpression on lifespanin C. elegans and Drosophila. Nature 2011; 477 :482-485.
• [25] Haigis MC, Sinclair DA. Mammalian sirtuins: biological insightsand disease relevance. Annu Rev Pathol 5: 253-295.[PubMed]
• [26] Nakao M. Epigenetics: interaction of DNA methylation andchromatin. Gene 2001; 278: 25-31.
• [27] Hernick M, Fierke CA. Zinc hydrolases: the mechanisms ofzinc-dependent deacetylases. ABB 2005; 433: 71–84.
• [28] Tanner KG, Landry J, Sternglanz R, Denu JM. Silent informationregulator 2 family of NAD- dependent histone/proteindeacetylases generates a unique product, 1-O-acetyl-ADPribose.PNAS 2000; 97: 14178–14182.
• [29] Sauve AA. Sirtuin chemical mechanisms. BBA 2010; 1804:1591–1603.
• [30] Sinclair DA, Guarente L. Unlocking the secrets of longevitygenes. Sci Am 2006; 294: 48–51.
• [31] Mai A, Massa S, Rotili D, Cerbara I, Valente S, Pezzi R, et al.Histone deacetylation in epigenetics: an attractive target foranticancer therapy. Med Res Rev 2005; 25: 261-309.[PubMed][Crossref]
• [32] Sutherland JE, Costa M. Epigenetics and the environment. AnnN Y Acad Sci 2003; 983: 151-160.
• [33] Garfinkel MD, Sollars VE, Lu X, Ruden DM. Multigenerationalselection and detection of altered histone acetylation andmethylation patterns: toward a quantitative epigenetics inDrosophila. Methods Mol Biol 2004; 287:151-168.
• [34] Cerutti H, Casas-Mollano JA. Histone H3 phosphorylation:universal code or lineage specific dialects? Epigenetics 2009; 4: 71-75.[Crossref][PubMed]
• [35] Kassner I, Barandun M, Fey M, Rosenthal F, Hottiger MO.Crosstalk between SET7/9-dependent methylation andARTD1-mediated ADP-ribosylation of histone H1.4. EpigeneticsChromatin 2013; 6:1.
• [36] Murayama A, Ohmori K, Fujimura A, Minami H, Yasuzawa-Tanaka K, Kuroda T, et al. Epigenetic control of rDNA lociin response to intracellular energy status. Cell 2008; 133:627-639.
• [37] Zhou Y, Schmitz KM, Mayer C, Yuan X, Akhtar A, Grummt I.Reversible acetylation of the chromatin remodelling complexNoRC is required for non-coding RNA-dependent silencing. NatCell Biol 2009 ; 11 :1010-1016.[PubMed][Crossref]
• [38] Li Y, Tollefsbol TO. p16(INK4a) suppression by glucoserestriction contributes to human cellular lifespan extensionthrough SIRT1-mediated epigenetic and genetic mechanisms.PLoS One 2011; 6:e17421.[Crossref]
• [39] Mulligan P, Yang F, Di Stefano L, Ji JY, Ouyang J, Nishikawa JL, etal. A SIRT1-LSD1 corepressor complex regulates Notch targetgene expression and development. Mol Cell 2011; 42:689-699.[Crossref]
• [40] Serrano L, Martínez-Redondo P, Marazuela-Duque A, VazquezBN, Dooley SJ, Voigt P, et al. The tumor suppressor SirT2regulates cell cycle progression and genome stability bymodulating the mitotic deposition of H4K20 methylation.Genes Dev 2013; 27: 639-653.[Crossref]
• [41] McCord RA, Michishita E, Hong T, Berber E, Boxer LD, KusumotoR, et al. SIRT6 stabilizes DNA-dependent protein kinase atchromatin for DNA double-strand break repair. Aging 2009; 1:109-121.
• [42] Peng L, Yuan Z, Ling H, Fukasawa K, Robertson K, OlashawN, et al. SIRT1 deacetylates the DNA methyltransferase 1(DNMT1) protein and alters its activities. Mol Cell Biol 2011; 31:4720-4734.[PubMed][Crossref]
• [43] Zocchi L, Sassone-Corsi P. SIRT1-mediated deacetylation ofMeCP2 contributes to BDNF expression. Epigenetics 2012;7:695-700.[Crossref]
• [44] Eskandarian HA, Impens F, Nahori MA, Soubigou G, CoppéeJY, Cossart P, et al. A role for SIRT2-dependent histone H3K18deacetylation in bacterial infection. Science 2013; 341:1238858.
• [45] Du J, Jiang H, Lin H. Investigating the ADP-ribosyltransferaseactivity of sirtuins with NAD analogues and 32P-NAD.Biochemistry 2009; 48: 2878-2890.[PubMed][Crossref]
• [46] Fahie K, Hu P, Swatkoski S, Cotter RJ, Zhang Y, Wolberger C.Side chain specificity of ADP-ribosylation by a sirtuin. FEBS J2009; 276: 7159-7176.
• [47] Cantó C, Sauve AA, Bai P. Crosstalk between poly(ADP-ribose)polymerase and sirtuin enzymes. Mol Aspects Med 2013; 34:1168-1201.[PubMed][Crossref]
• [48] Osada T, Rydén AM, Masutani M. Poly(ADP-ribosylation)regulates chromatin organization through histone H3modification and DNA methylation of the first cell cycle ofmouse embryos. Biochem Biophys Res Commun 2013; 434:15-21.
• [49] Martinez-Zamudio R, Ha HC. Histone ADP-ribosylationfacilitates gene transcription by directly remodelingnucleosomes. Mol Cell Biol 2012; 32: 2490-2502.[Crossref]
• [50] Merrick CJ, Duraisingh MT. Plasmodium falciparum Sir2: anunusual sirtuin with dual histone deacetylase and ADP-ribosyltransferaseactivity. Eukaryot Cell 2007; 6 : 2081-2091.[Crossref]
• [51] García-Salcedo JA, Gijón P, Nolan DP, Tebabi P, PaysE. A chromosomal SIR2 homologue with both histoneNAD-dependent ADP-ribosyltransferase and deacetylaseactivities is involved in DNA repair in Trypanosoma brucei.EMBO J 2003; 22: 5851-5862.[Crossref]
• [52] Etchegaray JP, Zhong L, Mostoslavsky R. The histonedeacetylase SIRT6: at the crossroads between epigenetics,metabolism and disease. Curr Top Med Chem 2013; 13:2991-3000.
• [53] Michishita E, McCord RA, Berber E, Kioi M, Padilla-Nash H,Damian M, et al. SIRT6 is a histone H3 lysine 9 deacetylase thatmodulates telomeric chromatin. Nature 2008; 452: 492-496.
• [54] Liszt G, Ford E, Kurtev M, Guarente L. Mouse Sir2 homologSIRT6 is a nuclear ADP-ribosyltransferase. J Biol Chem 2005;280: 21313-21320.
• [55] Mao Z, Hine C, Tian X, Van Meter M, Au M, Vaidya A, et al. SIRT6promotes DNA repair under stress by activating PARP1. Science2011; 332: 1443-1446.
• [56] Holness MJ, Caton PW, Sugden MC. Acute and long-termnutrient-led modifications of gene expression: potential roleof SIRT1 as a central co-ordinator of short and longer-termprogramming of tissue function. Nutrition 2010; 26: 491-501.[Crossref]
• [57] Patani N, Jiang WG, Newbold RF, Mokbel K. Histone-modifiergene expression profiles are associated with pathological andclinical outcomes in human breast cancer. Anticancer Res 2011;31: 4115-4125.[PubMed]
• [58] Singh SK, Williams CA, Klarmann K, Burkett SS, Keller JR,Oberdoerffer P. Sirt1 ablation promotes stress-induced loss ofepigenetic and genomic hematopoietic stem and progenitorcell maintenance. J Exp Med 2013; 210: 987-1001.
• [59] Hasegawa K, Wakino S, Simic P, Sakamaki Y, Minakuchi H,Fujimura K, et al. Renal tubular Sirt1 attenuates diabeticalbuminuria by epigenetically suppressing Claudin-1 overexpressionin podocytes. Nat Med 2013; 19: 1496-1504.[Crossref]
• [60] Clarke NE, Belyaev ND, Lambert DW, Turner AJ. Epigeneticregulation of angiotensin-converting enzyme 2 (ACE2) by SIRT1under conditions of cell energy stress. Clin Sci (Lond) 2014;126: 507-516.
• [61] Marquardt JU, Fischer K, Baus K, Kashyap A, Ma S, Krupp M,et al. Sirtuin-6-dependent genetic and epigenetic alterationsare associated with poor clinical outcome in hepatocellularcarcinoma patients. Hepatology 2013; 58: 1054-1064.[PubMed][Crossref]
• [62] Paredes S, Villanova L, Chua KF. Molecular Pathways: EmergingRoles of Mammalian Sirtuin SIRT7 in Cancer. Clin Cancer Res2014; 20: 1741-1746.[Crossref]
• [63] Marques SC, Lemos R, Ferreiro E, Martins M, de Mendonça A,Santana I, et al. Epigenetic regulation of BACE1 in Alzheimer’sdisease patients and in transgenic mice. Neuroscience 2012;220: 256-266.
• [64] Tiberi L, van den Ameele J, Dimidschstein J, Piccirilli J, GallD, Herpoel A, et al. BCL6 controls neurogenesis throughSirt1-dependent epigenetic repression of selective Notchtargets. Nat Neurosci 2012 ; 15 :1627-1635.[Crossref]
• [65] Albani D, Polito L, Forloni G. Sirtuins as novel targets forAlzheimer’s disease and other neurodegenerative disorders:experimental and genetic evidence. J Alzheimers Dis 2010; 19:11-26.
• [66] Mai A. Small-molecule chromatin-modifying agents:therapeutic applications. Epigenomics 2010; 2 : 307-324.[Crossref][PubMed]
• [67] Huber K, Superti-Furga G. After the grape rush: sirtuins asepigenetic drug targets in neurodegenerative disorders. BioorgMed Chem 2011; 19: 3616-3624.[Crossref]
• [68] Outeiro TF, Kontopoulos E, Altmann SM, Kufareva I,Strathearn KE, Amore AM, et al. Sirtuin 2 inhibitors rescuealpha-synuclein-mediated toxicity in models of Parkinson’sdisease. Science 2007; 317: 516-519.
• [69] Chopra V, Quinti L, Kim J, Vollor L, Narayanan KL, EdgerlyC, et al. The sirtuin 2 inhibitor AK-7 is neuroprotective inHuntington’s disease mouse models. Cell Rep 2012; 2:1492-1497.[Crossref]
• [70] Donmez G, Outeiro TF SIRT1 and SIRT2: emerging targets inneurodegeneration.. EMBO Mol Med 2013; 5: 344-352.[Crossref]
• [71] Bonda DJ, Lee HG, Camins A, Pallàs M, Casadesus G, Smith MA,et al. The sirtuin pathway in ageing and Alzheimer disease:mechanistic and therapeutic considerations.. Lancet Neurol2011; 10: 275-279.[Crossref]
• [72] Cosín-Tomás M, Alvarez-López MJ, Sanchez-Roige S, LalanzaJF, Bayod S, Sanfeliu C, et al . Epigenetic alterations inhippocampus of SAMP8 senescent mice and modulation byvoluntary physical exercise.. Front Aging Neurosci 2014; 6:51.
• [73] Kim D, Nguyen MD, Dobbin MM, Fischer A, Sananbenesi F,Rodgers JT, et al. SIRT1 deacetylase protects against neurodegenerationin models for Alzheimer’s disease and amyotrophiclateral sclerosis.. EMBO J 2007; 26: 3169-3179.[PubMed][Crossref]
• [74] Chang J, Rimando A, Pallas M, Camins A, Porquet D, Reeves J,et al. Low-dose pterostilbene, but not resveratrol, is a potentneuromodulator in aging and Alzheimer’s disease. NeurobiolAging 2012; 33: 2062-2071.[Crossref]
• [75] Karagiannis TC, Ververis K. Pathobiol. Potential of chromatinmodifying compounds for the treatment of Alzheimer’sdisease. Aging Age Relat Dis 2012; 2.
• [76] Feldman JL, Dittenhafer-Reed KE, Denu JM. Sirtuin catalysis andregulation. J Biol Chem 2012; 287: 42419-42427.
• [77] Polito L, Kehoe PG, Forloni G, Albani D.The molecular geneticsof sirtuins: association with human longevity and age-relateddiseases. Int J Mol Epidemiol Genet 2010; 1: 214-225.

Identifiers

DOI

10.2478/end-2014-0001