Sirtuins ADP 1 PARP-1

ISSN 1007-7626 CN 11-3870 / Q http / / cjbmb bjmu edu cn Chinese Journal of Biochemistry and Molecular Biology 2012 1 28 1 9 ~ 17 Sirtuins PARP-1 * 210095 Sirtuins 7 SIRT1 ~ SIRT7 NAD + 7 p53 FOXO Sirtuins Sirtuins ADP poly ADP-ribose polymerase PARP ADP 1 PARP-1 DNA NAD + Sirtuins PARP-1 Sirtuins PARP-1 Sirtuins PARP-1 Sirtuins ADP 1 PARP-1 Q255 Interplay of Sirtuins and PARP-1 in Cell Apoptosis WEI Quan-Wei SHI Fang-Xiong * College of Animal Science and Technology Nanjing Agricultural University Nanjing 210095 China Abstract The silent information regulator SIR genes Sirtuins are highly conserved NAD + - dependent enzymes from bacteria to mammals which include seven family members as SIRT1 to SIRT7 with defined subcellular localizations Sirtuins are actively involved in the regulation of gene expression and cellular development with their histone deacetylase activity to modulate transcription factors like p53 and FOXO etc Sirtuins have also been implicated for key roles in certain physiological processes especially linked to lifespan expansion as being attentioned PARP-1 is a member of poly ADP-ribose polymerase PARP family which is also comprised of NAD + -dependent enzymes and play vital roles in multiple cellular processes such as DNA repair and maintenance of the genomic integrity As the interplay of sirtuins and PARP-1 in cellular development has been extensively reported this article reviews the biological characteristics of the sirtuins family members and their functions with PARP-1 in the pathways and the process of cell apoptosis Key words Sirtuins PARP-1 cell apoptosis interplay 2 silent information regulator 2 SIR2 NAD + 2011-09-29 2011-10-26 HDAC 1 SIR2 Sirtuins Sirtuins Sirtuins No 31172206 NAD + / Ⅲ E-mail fxshi@ njau edu cn No 31172206 * Tel / Fax 025-84399112 E-mail fxshi@ niau edu cn Received September 29 2011 Accepted October 26 2011 Supported by National Natural Science Foundation of China * Corresponding author Tel / Fax 025-84399112

10 28 2 Sirtuins Table 1 Main characteristic of mammalian sirtuins NAD + Sirtuins Enzyme categorization Subcellular Molecular 1 location mass / kd Sirtuins SIRT1 Deacetylase Cytoplasm and 62 0 nucleus Sirtuins SIRT2 Deacetylase Cytoplasm and 41 5 nucleus ADP poly ADP-ribose polymerase 1 Sirtuins SIRT3 Deacetylase and ADPribosyltransferase Mitochondria 43 6 SIRT4 ADP-ribosyltransferase Mitochondria PARP 35 2 SIRT5 Deacetylase Mitochondria 33 9 SIRT6 Deacetylase and ADPribosyltransferase Nucleus 39 1 PARP-1 ADP 90% DNA SIRT7 Deacetylase Nucleus 44 8 DNA ADP DNA 1 2 Sirtuins Sirtuins apoptosis PARP-1 Sirtuins SIRT3 4 5 N NAD + Sirtuins PARP-1 SIRT3 PARP-1 Sirtuins 12 7 Sirtuins Sirtuins PARP-1 SIRT6 Sirtuins PARP-1 SIRT7 SIRT1 2 2 13 Sirtuins 2 Sirtuins NAD + 1 1 Sirtuins nicotinamide NAM Sirtuins 7 NAD + ADP SIRT1 ~ SIRT7 5 7 14 Sirtuins NAM SIRT1 2 6 Sirtuins 15 NAM NAD + 7 SIRT1 SIRT2 SIRT3 4 5 7 nicotinamide phosphoribosyltransferase NAMPT 6 nicotinamide mononucleotide NMN nicotinamide sirtinol 1 2- -3H- nicotinamide mononucleotide adenylyl transferase 2 1-b -3- splitomicin Nmnat NMN NAD + 16 NAM NAD Sirtuins Ⅲ 7 Sirtuins + SIRT4 nicotinamide phosphoribosyltransferase Nampt NAD nicotinamide 8 SIRT1 SIRT6 mononucleotide adenylyltransferase Nmnat ADP 9 Sirtuins NAM NAD + SIRT1 Table 1 10 11 NAD + Sirtuins

1 Sirtuins PARP-1 11 NAD + NAM NAM Sirtuins 17 NAM NAD + Sirtuins NAD + Sirtuins 2 DNA 1 NAMPT NAD + 2 DNA SIRT1 PARP-1 DBD NAD + SIRT3 4 5 3 DNA PARP-1 18 Sirtuins Fig 1 10 19 Fig 1 Enzymatic activity of Sirtuins during the process of protein deacetylation The deacetylation reaction of sirtuins consists of two steps The first Sirtuins deacetylate the target proteins via cleavage of nicotinamide-adenine-dinucleotide NAD + to release nicotinamide NAM The second acetyl group is transferred to the ADP-ribose ADPR moiety of NAD + to generate O-acetyl-ADPR the deacetylated substrate Deacetylation process can be inhibited by NAM which can also reverse the reaction to reproduce NAD + NAM is usually converted to nicotinamide mononucleotide NMN by nicotinamide phosphoribosyl-transferase Nampt which is a NAD salvage enzyme Then nicotinamide mononucleotide adenyltransferase Nmnat can regenerate NAD + from NMN 2 PARP-1 2 1 PARP-1 PARP-1 ADP poly ADP-ribose polymerase PARP PARP-1 24 DNA 3 1 014 1 Fig 3 DNA 113 kd 8 0 ~ 9 8 3 PARP-1 DNA N DNA DNAbinding domain DBD 46 kd N 1 ~ ADP DNA PARP 372 2 1 DNA DNA nuclear localization sequence NLS 2 Zn fingure NLS caspase 20 DNA PARP auto-modification domain 22 kd 374 ~ 524 PARP-1 ADP PARP 1 BRCT breast cancer associated protein C-terminal PARP-1 C- 525 ~ 1 014 catalytic domain 54 kd NAD + ADP 859 ~ 908 100% PARP Fig 2 21 C NAD + PARP-1 Fig 2 4 20 21 2 2 PARP-1 DNA 30 PARP-1 PARP-1 DNA PARP-1 PAR PARP-1 NAD + 22 PARP-1 N DNA DBD capase-3 caspase-3 PARP-1 BRCT C PAR 23 PARP-1 DNA DNA

12 28 Fig 2 Structural and functional organization of human PARP-1 human PARP-1 contains three main domains the NH 2 -terminal DNA-binding domain DBD with two zinc fingers Zn I and Zn Ⅱ Automodification domain AMD with a breast cancer susceptibility protein C terminus BRCT motif Catalytic domain with the NAD + -binding site The DBD also contains a NLS in which the caspase-cleavage site DVED is located BRCT motif is very common in repair and cell cycle proteins PARP-1 can bind to some proteins through the BRCT motif The active site of PARP-1 in the C-terminus contains a highly conserved sequence residues 859-908 which is named PARP signature 25 DNA PARP-1 PARP caspase PARP-1 PARP-1 NAD + / PARP-1 ATP 26 DNA Fig 3 22 25 ~ 27 Fig 3 Determination of cell fates by PARP-1 Levels of stress determine the cell fates cell survival cell apoptosis or cell necrosis Depending on the stress intensity stress signal can trigger three different pathways If the DNA damage is mild PARP-1 is activated to facilitates DNA repair then cell is survival More severe stress may lead to unrepairable DNA damage activated PARP-1 is cleaved by p53 and then the cell fate is determined by the p53-dependent apoptotic pathway Serious DNA damage may cause PARP overactivation which may deplete cellular NAD + / ATP storage NAD + / ATP exhaustion may block cell apoptosis and lead to necrosis The inhibition of PARP-1 in cells of serious DNA damage may preserve cellular energy storeage and lead to apoptosis p53 FOXO DNA 3 Sirtuins Sirtuins

1 Sirtuins PARP-1 13 p53 C / EBPα SIRT1 SIRT1 40 p53 SIRT1 SIRT7 SIRT1 TATA 28 p53 Sirtuins TAFI68 RNA DNA SIRT1 SIRT7 I 41 SIRT7 RNA I p53 42 SIRT3 SIRT5 29 SIRT1 p53 p53 DNA DNA 44 29 30 SIRT1 SIRT2 SIRT6 p53 31 SIRT6 FOXO SIRT6 45 Sirtuins FOXO NAD + DNA NAD + SIRT1 Foxo1 Sirtuins SIRT1 Foxo3a Foxo4 32 NAD + SIRT1 Foxo3a 46 DNA Sirtuins 33 Fig 4 37 47 ~ 49 Sirtuins 4 PARP-1 SIRT1 PARP-1 FOXO p53 DNA sirt1 caspase 34 Sirtuins p53 p53 p53 caspase caspase-3 35 FOXO Foxo1 Foxo4 PARP-1 caspase3 p89 Sirtuins p21 PARP-1 DNA SIRT1 Foxo1 Foxo4 BAX BCL 39 43 SIRT6 DNA ATP p27 PARP-1 DNA 45α Fig 3 PARP-1 caspase 32 DNA SIRT1 p300 p300 PARP-1 apoptosis-inducing factor FOXO p53 36 AIF DNA SIRT2 Foxo3a ROS 50 AIF 37 SIRT1 SIRT7 p53 51 p53 38 RNA SIRT1 PARP-1 p53 DNA

14 28 Fig 4 Relationship between Sirtuins and apoptosis factors during the process of apoptosis C / EBPα promotes expression level of Sirtuins SIRT1 by directly binding to the promoter of Sirtuins Sirtuins may takes part in FOXO-mediated or p53-dependent apoptosis Because of deacetylation effect of Sirtuins activities of FOXO family members p300 and p53 are increased in response to various stresses such as oxidative stress heat shock and UV radiation p53 and FOXO members acetylation by p300 and deacetylation by Sir2 affects the downstream factors which regulate whether cells progress towards growth or apoptosis PARP-1 p53 mrna PARP-1 DNA ADP p53 Sirtuins DNA p53 52 Sirtuins DNA PARP-1 p53 ADP DNA p53 p53 PARP-1 caspase-3 p53 55 p53 ADP PARP-1 Sirtuins NF-κB p53 53 PARP-1 p53 56 PARP-1 p53 DNA PARP-1 p53 54 DNA SIRT1 PARP-1 5 Sirtuins PARP PARP-1 DNA 57 Science 1 Sirtuins 1 SIRT6 PARP-1 PARP-1 Sirtuins DNA 58 PARP-1 SIRT1 PARP-1 Sirtuins NAD +

1 Sirtuins PARP-1 15 ADP NAD + Sirtuins PARP-1 Sirtuins NAD + 59 PARP-1 NAD + Sirtuins 60 PARP-1 PARP-1 caspase Fig 4 61 NAD + Fig 5 Interactions between PARP-1 and sirtuindependent processes in cells during apoptosis NAD + PARP-1 NAD Deacetylase activities of Sirtuins are NAD + -dependent so + AIF poly ADP-ribose metabolism may downregulate Sirtuins 62 PARP-1 Sirtuins through NAD + depletion The formed nicotinamide NAD + NAM has the inhibition effect on Sirtuins p53 20 deacetylation by Sirtuins may affect DNA-binding activity of p53 which is the key regulator of p53-mediated apoptosis DNA PARP-1 pathway Stress may activate PARP-1 through DNA damage DNA Sirtuins as well as the acetylation of PARP-1 Poly ADP-ribosyl 63 PARP-1 Sirtuins ation by PARP-1 may reduce cellular level of NAD + and NAD + NAM increase NAM The increased level of NAM have the PARP-1 Sirtuins 7 PARP- inhibition effect on Sirtuins and PARP-1 activities These 1 NAD + Sirtuins changes may lead to cell apoptosis or cell survival To PARP-1 SIRT1 counteract the effect of PARP-1 Sirtuins may also Fig 5 55 59 60 64 65 deacetylate PARP-1 thereby inhibit activity of PARP-1 Hence this function of Sirtuins helps to maintain cellular 6 NAD + levels and Sirtuins activities and promotes cell survival in response to verious stress DNA PARP-1 Sirtuin PARP-1 PARP-1 66 Sirtuins PARP-1 PARP-1 DNA Sirtuins PARP-1 Sirtuins References DNA PARP-1 Sirtuins PARP-1 J Altern Med Rev 2010 15 3 245-263 PARP-1 Sirtuins Sirtuins PARP-1 1 Imai S Armstrong CM Kaeberlein M et al Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase J Nature 2000 403 6771 795-800 2 Kelly G A review of the sirtuin system its clinical implications and the potential role of dietary activators like resveratrol part 1 3 Kraft KS Ruenitz PC Bartlett MG Carboxylic acid analogues of tamoxifen Z -2- p- 1 2-diphenyl-1-butenyl phenoxy -N N- dimethylethylamine Estrogen receptor affinity and estrogen antagonist effects in MCF-7 cells J J Med Chem 1999 42

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