Article thumbnail

Sirtuins: Molecular Traffic Lights in the Crossroad of Oxidative Stress, Chromatin Remodeling, and Transcription

By Ramkumar Rajendran, Richa Garva, Marija Krstic-Demonacos and Constantinos Demonacos


Transcription is regulated by acetylation/deacetylation reactions of histone and nonhistone proteins mediated by enzymes called KATs and HDACs, respectively. As a major mechanism of transcriptional regulation, protein acetylation is a key controller of physiological processes such as cell cycle, DNA damage response, metabolism, apoptosis, and autophagy. The deacetylase activity of class III histone deacetylases or sirtuins depends on the presence of NAD+ (nicotinamide adenine dinucleotide), and therefore, their function is closely linked to cellular energy consumption. This activity of sirtuins connects the modulation of chromatin dynamics and transcriptional regulation under oxidative stress to cellular lifespan, glucose homeostasis, inflammation, and multiple aging-related diseases including cancer. Here we provide an overview of the recent developments in relation to the diverse biological activities associated with sirtuin enzymes and stress responsive transcription factors, DNA damage, and oxidative stress and relate the involvement of sirtuins in the regulation of these processes to oncogenesis. Since the majority of the molecular mechanisms implicated in these pathways have been described for Sirt1, this sirtuin family member is more extensively presented in this paper

Topics: Review Article
Publisher: Hindawi Publishing Corporation
OAI identifier:
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles


  1. A .L .C l a y t o n ,C .A .H a z z a l i n ,a n dL .C .M a h a d e v a n , “Enhanced histone acetylation and transcription: a dynamic perspective,”MolecularCell,vol.23,no.3,pp.289–296,2006.
  2. (2010). A .V i l l a g r a ,E .M .S o t o m a y o r ,a n dE .S e t o ,“ H i s t o n ed e a c e t y -lases and the immunological network: implications in cancer and inflammation,”
  3. (2009). A c-Myc-SIRT1 feedback loop regulates cell growth and transformation,”
  4. (2008). A dual role of p53 in the control of autophagy,”
  5. (2007). A l l i s ,S .L .B e r g e r ,J .C o t ee ta l . ,“ N e wn o m e n c l a t u r e for chromatin-modifying enzymes,”
  6. (2008). A role for SIRT1 in cell growth and chemoresistance
  7. (2008). A role for the NADdependent deacetylase Sirt1 in the regulation of autophagy,”
  8. (2007). A therapeutic role for sirtuins in diseases of aging?”
  9. (2003). A unified nomenclature for yeast autophagy-related genes,”
  10. A.Brunet,L.B.Sweeney,J.F.Sturgilletal.,“Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase,”Science,vol.303,no.5666,pp.2011–2015,2004.
  11. (2005). Acetylation and deacetylation of non-histone proteins,”
  12. (2009). Acetylation goes global: the emergence of acetylation biology,”
  13. (2008). Acetylation of Sirt2 by p300 attenuates its deacetylase activity,”
  14. (2007). Active regulator of
  15. (2008). Aging: a sirtuin shake-up?”
  16. (2008). anabolism:therapeuticpotentialforoxidativestressin ageing and alzheimer’s disease,”
  17. (2008). and A.Brunet,“TheFoxO code,”
  18. (2006). Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes,”
  19. (2008). AsSIRTing the DNA damage response,”
  20. (2010). Autophagy in health and disease. 1. Regulation and significance of autophagy: an overview,”
  21. (2010). Autophagy regulation by p53,”
  22. Bamman et al., “SIRT1issignificantlyelevatedinmouseandhumanprostate cancer,”CancerResearch,vol.67,no.14,pp.6612–6618,2007.
  23. (2009). Biochemical pathways that regulate acetyltransferase and deacetylase activity in mammalian cells,”
  24. (2003). C.C.Fjeld,W.T.Birdsong,andR.H.Goodman,“Differential binding of NAD+ and NADH allows the transcriptional corepressor carboxyl-terminal binding protein to serve as a metabolic sensor,”
  25. (2009). C.Das,M.S.Lucia,K.C.Hansen,andJ.K.Tyler,“CBP/p300-mediated acetylation of histone H3
  26. (2007). C.Fleuriel etal., “Metabolic regulation of SIRT1 transcription via a HIC1:CtBP corepressor complex,”
  27. (2009). C.L.BrooksandW.Gu,“HowdoesSIRT1affectmetabolism, senescence and cancer?”
  28. (2004). Calorie restriction extends yeast life span by lowering the level
  29. (2005). Cancer-specific functions of SIRT1 enable human epithelial cancer cell growth and survival,”
  30. (2009). Carboxy-terminal phosphorylation of SIRT1 by protein kinase CK2,”
  31. (2003). Cardiac hypertrophy and histone deacetylase-dependent transcriptional repression mediated by the atypical homeodomain protein Hop,”
  32. (2007). Carobbio et al., “Regulation of insulin secretion by SIRT4, a mitochondrial ADPribosyltransferase,”
  33. (2006). Caspase-mediated changes in Sir2α during apoptosis,”
  34. (2003). Class II histone deacetylases: versatile regulators,”
  35. (2003). CtBP/BARS: a dualfunction protein involved in transcription co-repression and Golgi membrane fission,”
  36. (2010). Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity,”
  37. (2002). Deacetylase enzymes: biological functions and the use of small-molecule inhibitors,”
  38. deacetylates FOXO3a in response to oxidative stress and caloric restriction,”
  39. (2010). Deacetylation of FoxO by Sirt1 plays an essential role in mediating starvation-induced autophagy in cardiac myocytes,”
  40. (2007). Deacetylation of the retinoblastoma tumour suppressor protein by SIRT1,”
  41. (2006). Distinct and overlapping roles for E2F family members in transcription, proliferation and apoptosis,” Current Molecular Medicine,v o l .6 ,n o .7 ,p p .
  42. (2009). Distinct HIC1-SIRT1-p53 loop deregulation in lung squamous carcinoma and adenocarcinoma patients,”
  43. (2008). Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter
  44. (2007). Dynamic FoxO transcription factors,”
  45. (2009). Dynamics and diversity in autophagy mechanisms: lessons from yeast,”
  46. (2011). Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications,”
  47. (2010). DYRK1A and DYRK3 promote cell survival through phosphorylation and activation of SIRT1,”
  48. (2007). E.WeteringsandD.J.Chen,“DNA-dependentproteinkinase in nonhomologous end joining: a lock with multiple keys?”
  49. Energetic cell sensors: a key to metabolic homeostasis,” Trends in EndocrinologyandMetabolism,vol.21,no.2,pp.75–82,2010.
  50. (2010). Epigenetic histone code and autoimmunity,”
  51. (2009). Epigenetics: a molecular link between environmental factors and type 2 diabetes,”
  52. (2007). Extension of human cell lifespan by nicotinamide phosphoribosyltransferase,”
  53. (2010). Foxo3a expression and acetylation regulate cancer cell growth and sensitivity to cisplatin,”
  54. (2007). Functions of sitespecific histone acetylation and deacetylation,”
  55. (2008). G.Boily,S.Bazinetetal.,“sirt1-nullmicedevelop an autoimmune-like condition,”
  56. (2008). genome instability, and tumorigenesis in SIRT1 mutant mice,”
  57. (2006). Genomic instability and aging-like phenotype in the absence of mammalian SIRT6,”
  58. (2008). Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of
  59. (2008). h a o ,J .P .K r u s e ,Y .T a n g ,S .Y .J u n g ,J .Q i n ,a n dW
  60. (2005). Histone deacetylase inhibitors: new drugs for the treatment of inflammatory diseases?”
  61. (2009). Histone deacetylase-2 and airway disease,”
  62. (2005). Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors,”
  63. (2007). Histone deacetylases—an important class of cellular regulators with a varietyoffunctions,”AppliedMicrobiologyandBiotechnology,
  64. (2008). How to live long and prosper: autophagy, mitochondria,
  65. hSIR2SIRT1 functions as an NAD-dependent p53
  66. (2010). Human SIRT6 promotes DNA end resection through
  67. (2010). Inhibitors to understand molecular mechanisms of NAD+-dependent deacetylases (sirtuins),”
  68. interacts with p73 and suppresses p73-dependent transcriptional activity,”
  69. (2007). Interphase nucleo-cytoplasmic shuttling and localization of SIRT2 during mitosis,”
  70. (2008). Interplay among BRCA1, SIRT1, and survivin during BRCA1-associated tumorigenesis,”
  71. (2009). Involvement of SIRT7 in resumption of rDNA transcription at the exit from mitosis,”
  72. (2008). J.Bruno,E.Easlon et al., “Tissue-specific regulation of SIRT1 by calorie restriction,”
  73. (2008). JNK2-dependent regulation of SIRT1 protein stability,”
  74. (2008). K.M.Jacobs,J.D.Pennington,K.S.Bishtetal.,“SIRT3interacts with the daf-16 homolog FOXO3a in the mitochondria, as well as increases FOXO3a dependent gene expression,”
  75. (2009). Kaempferol induces apoptosis in two different cell lines via Akt inactivation, bax and SIRT3 activation, and mitochondrial dysfunction,”
  76. (2009). Kr¨ amer, “HDAC2: a critical factor in health and disease,”
  77. (2001). La Thangue, “Acetylation control of the retinoblastomatumour-suppressorprotein,”Nature
  78. (2010). Linking calorie restriction to longevity through sirtuins and autophagy: any role for TOR,”
  79. (2008). Localization of mouse mitochondrial SIRT proteins: shift of SIRT3 to nucleus by co-expression with SIRT5,”
  80. (2004). Mammalian SIRT1 represses forkhead transcription factors,”
  81. (2006). Mammalian sirtuins— emerging roles in physiology, aging, and calorie restriction,”
  82. (2010). Mammalian sirtuins: biological insights and disease relevance,” Annual Review of Pathology:
  83. (2005). Mechanism of sirtuin nhibition by nicotinamide: altering the NAD+ cosubstrate specificity of a
  84. (2008). miR-34a repression of SIRT1 regulates apoptosis,”
  85. (2005). Mitochondria, oxidants, and aging,”
  86. (2007). Mitotic regulation of SIRT2 by cyclin-dependent kinase 1-dependent phosphorylation,”
  87. (2004). Modulation of NF-κB-dependent transcription and cell survival by the SIRT1 deacetylase,”
  88. (2001). Molecular dissection of autophagy: two ubiquitin-like systems,”
  89. (2009). mTOR’s role in ageing: protein synthesis or autophagy?”
  90. Multiple roles of HDAC inhibition in neurodegenerative conditions,”
  91. (2003). Multiple tumor suppressor pathways negatively regulate telomerase,”
  92. N.Tavernarakis,A.Pasparaki,E.Tasdemir,M.C.Maiuri,and G.Kroemer,“Theeffectsofp53onwholeorganismlongevity aremediatedbyautophagy,”Autophagy,vol.4,no.7,pp.870– 873, 2008.Journal of
  93. (2010). NAD: a master regulator of transcription,”
  94. (2006). NAD+ and NADH in cellular functions and cell death,”
  95. (2009). NAD+, sirtuins, and cardiovascular disease,”
  96. (2009). NF-κB activation, dependent on acetylation/deacetylation, contributes to HIF-1 activity and migration of bone metastatic breast carcinoma cells,”
  97. (2009). Nucleosome positioning and gene regulation: advances through genomics,”
  98. (2004). Nutrient availability regulates SIRT1 through a forkhead-dependent pathway,”
  99. (2005). Nutrient control of glucose homeostasis through a complex of PGC-1α and
  100. (2006). Nutrition, sirtuins and aging,”
  101. (2005). o e l t e r - M a h l k n e c h t ,A .D .H o ,a n dU .M a h l k n e c h t , “Chromosomal organization and localization of the novel class IV human histone deacetylase 11 gene,”
  102. (2009). o n s ,F .R .d eV r i e s ,P .J .v a nD e nE l s e n ,B .T .H e i j m a n s
  103. (2002). Ohgi et al., “Transcription corepressor CtBP is an NAD+-regulated dehydrogenase,”
  104. (2004). Oxidative stress and mitochondrial function with aging—the effects of calorie restriction,”
  105. (2008). PCAF is an HIF-1α cofactor that regulates p53 transcriptional activity in hypoxia,”
  106. (2000). Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins,”
  107. (2005). Prospects: histone deacetylase inhibitors,”
  108. (2011). Protected from the inside: endogenous histone deacetylase inhibitors and the road to cancer,”
  109. (2010). Protein deacetylation by SIRT1: an emerging key post-translational modification in metabolic regulation,”
  110. (2007). Q.Jin,T.Yan,X.Ge,C.Sun,X.Shi,andQ.Zhai,“Cytoplasmlocalized SIRT1 enhances apoptosis,”
  111. (2006). R.B ilt on,E.T r ottier ,J .P ou yss´ egur,andM.C.Brahimi-Horn, “ARDent about acetylation and deacetylation in hypoxia signalling,”
  112. (2008). R.Pandithage,R.Lilischkis,K.Hartingetal.,“Theregulation of SIRT2 function by cyclin-dependent kinases affects cell motility,”
  113. (2009). Recent progress in the biology and physiology of sirtuins,”
  114. regulates autophagy and the transcription of autophagy genes,”
  115. regulates the function of the Nijmegen breakage syndrome protein,”
  116. (2009). Regulation mechanisms and signaling pathways of autophagy,”
  117. (2010). Regulation of global genome nucleotide excision repair by SIRT1 through xeroderma pigmentosum
  118. (2009). Regulation of hypoxia-inducible factor 2α signaling by the stressresponsive deacetylase sirtuin 1,”
  119. (2010). Regulation of SIRT1 in cellular functions: role of polyphenols,”
  120. (2007). Regulation of the HIF-1alpha stability by histone deacetylases,”
  121. (2008). Regulation of WRN protein cellular localization and enzymatic activities by SIRT1-mediated deacetylation,”
  122. (2007). Reversible acetylation of non histone proteins: role in cellular function and disease,”
  123. (2006). Reversible lysine acetylation controls the activity of the mitochondrial enzyme acetyl-CoA synthetase 2,”
  124. (2003). Role for human SIRT2 NAD-dependent deacetylase activityincontrolofmitoticexitinthecell cycle,”
  125. (2007). Role of NAD binding and catalytic residues in the C-terminal binding protein corepressor,”
  126. (2009). S.Rane,M.He,D.Sayedetal.,“DownregulationofMiR-199a derepresses hypoxia-inducible factor-1α and sirtuin 1 andJournal of Biomedicine and Biotechnology 13 recapitulates hypoxia preconditioning in cardiac myocytes,”
  127. (2000). Signaling to chromatin through historic modifications,”
  128. (2004). Silent information regulator 2 potentiates Foxo 1-mediated transcription through its deacetylase activity,”
  129. (2003). Sir2 regulates skeletal muscle differentiation as a potential sensor of the redox state,”
  130. (2010). SIRT1 and p53, effect on cancer, senescence and beyond,”
  131. (2008). SIRT1 longevity factor suppresses NF-κB-driven immune responses: regulation of aging via NF-κBa c e t y l a -tion?”
  132. (2008). SIRT1 overexpression antagonizes cellular senescence with activated ERK/S6k1 signaling in human diploid fibroblasts,”
  133. (2008). Sirt1 protects against oxidative stress-induced renal tubular cell apoptosis by the bidirectional regulation of catalase expression,”
  134. (2008). SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging,”
  135. SIRT1 regulates autoacetylation and histone acetyltransferase activity of TIP60,”
  136. (2010). SIRT1 suppresses activator protein-1 transcriptional activity and cyclooxygenase2 expression in macrophages,”
  137. (2008). SIRT1, an antiinflammatory and antiaging protein, is decreased in lungs of patients with chronic obstructive pulmonary disease,”
  138. SIRT1, is it a tumor promoter or tumor suppressor?”
  139. (2006). SIRT1: linking adaptive cellular responses to aging-associated changes in organismal physiology,”
  140. (2009). SIRT1: regulation of longevity via autophagy,”
  141. (2007). SIRT2, a tubulin deacetylase, acts to block the entry to chromosome condensation in response to mitotic stress,”
  142. Sirt3 blocks the cardiac hypertrophic response by augmenting Foxo3a-dependent antioxidant defense mechanisms in mice,”
  143. (2007). SirT3 is a nuclear NAD+-dependent histone deacetylase that translocates to the mitochondria upon cellular stress,”
  144. (2007). SIRT3 is pro-apoptotic and participates in distinct basal apoptotic pathways,”
  145. SIRT3, a mitochondrial sirtuin deacetylase, regulates mitochondrial function and thermogenesis in brown adipocytes,”
  146. (2008). SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin,”
  147. (2009). SIRT6 links histone H3 lysine 9 deacetylation to NF-κB-dependent gene expression and organismal life span,”
  148. (2008). Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice,”
  149. (2010). SIRTing out the link between autophagy and ageing,”
  150. (2010). Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha,” Molecular Cell,
  151. (2008). SIRTUIN 1: regulating the regulator,”
  152. (2010). Sirtuin 3, a new target of PGC-1α, plays an important role in the suppression
  153. (2010). Sirtuin chemical mechanisms,”
  154. (2010). Sirtuin function in longevity,”
  155. (2010). Sirtuin regulation in calorie restriction,”
  156. (2007). Sirtuins in mammals: insights into their biological function,”
  157. (2010). Sirtuins inhibitors: the approach to affinity and selectivity,”BiochimicaetBiophysicaActa,vol.1804,no.8,pp.
  158. (2007). Sirtuins: critical regulators at the crossroads between cancer and aging,”
  159. (2009). Song et al., “Overexpression of SIRT1 protects pancreatic β-cells against cytokine toxicity by suppressing the nuclear factor-κB signaling pathway,”
  160. (2011). Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome,”
  161. (2009). Stress-inducible regulation of heat shock factor 1 by the deacetylase
  162. (2007). Stressing the role of FoxO proteins in lifespan and disease,”
  163. (2008). Substrates and regulation mechanisms for the human mitochondrial sirtuins
  164. suppresses adipocyte differentiation by deacetylating FOXO1 and enhancing FOXO1’s repressive interaction with PPARγ,”
  165. (2005). Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation,”
  166. (2004). The c-MYC oncoprotein is a substrate of the acetyltransferases
  167. (2001). The emerging role of class II histone deacetylases,”
  168. (2010). The emerging role of lysine acetylation of non-nuclear proteins,”
  169. (2004). The interaction between FOXO and SIRT1: tipping the balance towards survival,”
  170. (2009). The many roles of histone deacetylases in development and physiology: implications for disease and therapy,”
  171. (2009). The NF-kappaB family of transcription factors and its regulation,”
  172. (2009). The R6 lines of transgenic mice: a model for screening new therapies for Huntington’s disease,”
  173. (2007). The regulation of nicotinamide adenine dinucleotide biosynthesis by Nampt/PBEF/visfatin
  174. (2008). The role of the RB tumour suppressor pathway in oxidative stress responses in the haematopoietic system,”
  175. (2010). The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways,”
  176. (2004). The Sir2 family of protein deacetylases,”
  177. (2008). The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth,”
  178. (2008). The SIRT2 deacetylase regulates autoacetylation of p300,”
  179. (2008). The ups and downs of SIRT1,”
  180. (2008). Transcription regulation by class III histone deacetylases (HDACs)—sirtuins,”
  181. (2001). Translating the histone code,”
  182. (2005). Triple layer control: phosphorylation, acetylation and ubiquitination of FOXO proteins,”
  183. (2006). Tsuchihara et al., “FOXO3adependent regulation of Puma in response to cytokine/growth factor withdrawal,”
  184. (2005). Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses,”
  185. (2007). u n k e l ,B .K .P e h ,Y .C .T a ne ta l . ,“ F u n c t i o no ft h eS I R T I protein deacetylase in cancer,”
  186. (2009). Vossio et al., “hSirT1-dependent regulation of the PCAF-E2F1-p73 apoptotic pathway in response to
  187. (2007). Y.Yang,W.Fu,J.Chenetal.,“SIRT1sumoylationregulatesits deacetylase activity and cellular response to genotoxic stress,”