死亡底物PARP与细胞凋亡

[]1000-8861(2002)03(S)-0177-05[]2002-03-18;[]2002-05-14[]赛　燕(1976-),女,山东威海市人,硕士生,主要从事化学毒物的损伤与防治研究。Tel:[phone];E-mail:[e-mail]赛　燕综述,刘　勇,董兆君审校(第三军医大学毒理学教研室,重庆400038)[　]　。PARP[poly(ADP-ribose)polymerase],。PARP。[]　;;;[]　R392.1;R392.12;R392.28　　　　　[]　ADeathsubstrate(PARP)andapoptosisSAIYan(DepartmentofToxicology,ThirdMilitaryMedicalUniversity,Chongqing400038,China)[Abstract]　Apoptosisisanimportantlifephenomenoninmutli-cellularorganism.ThecleavageofPoly(ADP-ribose)polymerase(PARP)isanmoleculareventoftheactivationofcysteineprotease,anditisalsoanearlymolecularmarkerofapoptosis.PARP,asadeathsubstrate,involvingintheexecutionofapoptosisisoneofthehottestareaofmodernbiologyinhomeandabroad.[Keywords]　deathsubstrate;poly(ADP-ribose)polymerase(PARP);caspase;　　(apoptosis),(commitment)(execution)2。Caspase,。,,caspase(terminaleffectorevents),,。PARPDNA,caspase-3,[1]。PARP,[1]。PARP,DNALADDER。PARP(deathsubstrate)。1　PARPPARP,。1994LazebnikPARPAsp-Gln-ValGly(DEVD↑G)。1998CynathiaRNA(PARP--),(PARP--)(PARP++):(PARP++)ADP;(PARP--)ADP[2]。ADP,PARP,PARP[3]。caspase-3PARPTNF[4,5]。PARP,,VP-16(etoposide)DNA(DNALADDER)[6]。Caspase-3PARPDEVD。PARPpoly(ADP-ribo-177S　　18　3　20026　　IMMUNOLOGICALJOURNALVol18No3June2002DOI:10.13431/j.cnki.immunol.j.20020202syl)ation。PARP[(ADP-)],。50。PARP1q41～q42,PARPcDNA3.7kb,(anopeningreadingframe)1014,113000u,3:N46000uDNA;22000u;54000u。PARP,(nicotinamide-adeninedinucleotide,NAD+),(ADP-ribose),ADP-ribose,DNA,PARPDNA,,PARP。,DNA,PARPDNA,,(),,。PARPDNA,PARP,DNA。PARP。PARPDNA(molecularsensor),。PAPPDNA,;;;。DNA,PAPP“”[7]。DNA,,,,PAPP,,,,,,;,。2　ADP2.1　PARP通过caspases的裂解剪切参与凋亡的发生　,,γ-,DNAPARP2(89000u24000u)。PARP,DNA,。,PARP3-(3-AB),NAD+,PARPDNA,PARP,DNA。PARP。PARPDNA,DNA,,DNA,PARPDNA,。,PARPcaspase,[7]。caspasecaspase-3PARP。caspase-3PARP。CaspaseDEVDPARP;CaspasePARPDNA,PARPDNADNA,PARPDNA[8]。2.2　Ca2+Mg2+依赖的核酸内切酶(DNASIL3)机制　DNA,DNA,Ca2+Mg2+DNA[9],PARPADPDNASIL3,DNASIL3DNA,PARP[10]。CaspasePARP,PARPADP,PARP,PARPCa2+Mg2+,DNA[11],PARPDNA,DNA[12]。2.3“遗传物质”储留机制　PARP,:PARP,DNA,“”,。:DNADNA-PK(DNA),caspase-3,160000u。178S18　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　20026,UI70000u(UI-70000u)caspase,40000u。UImRNA,DNA,mRNA,,“”,,。,PARP、DNA-PKDNAATM()caspase-3!caspase-3;,DNA,,。2.4　ATP和NAD+相关机制　。PARPNAD———。PARPNAD+ADP,NAD+ATP,,caspasePARPADP,ATPNAD+,[4]。NAD。PARPDEVDPARP,[4,5]。PARPNAD+ATP。。2.5　PARP裂解片段的抑制作用对凋亡的影响　PARP,PARPPARP。,PARP,80000uDNA。PARP,,85000u,DNA,DNA。caspasePARP24000u89000u[13]。89000uPARP,DNA,PARP。24000uPARPDNA2,DNA,。1998Smulson24000uPARPDNA[14],PARPDNA[15],PARPDNA,。2.6　PARP作用于P53启动凋亡发生　P53,,“”(molecularpoliceman),,G1-SG2-M(restrictionpoint)(check-point)。P53,P53,P53,,。1999Cynthin、SimbulanRosenthalP53,DNA,DNA,PARP,ADP,P53,P53[16],mRNA:PARPP53mRNAADP,P53。PARPP53,PARPP53DNA,P53[17]。caspase-3PARPP53。PARPP53,PARP(++)PARP(--),,P53,P53。NADPARP,P53,DNA。P53Bax、Fas。P53P53。PARPP53。2.7　PARP的自身修饰影响凋亡的发生　Negri,VP16Hela,PARP,,PARPPARP。1999HL60,PARPADP179S3　　　　　　　　　　　　　　　　　.PARPcaspase,PARPPARP,ADPcaspasePARP,PARP[8],。2.8　聚ADP核糖化的DNA断端保护作用机制　PARPADPPARPDNA,DNA。PARP,DNA,。PARPPARPADP,PARPDNA,。,PARP:图1　PARP参与凋亡的图解Fig1　MechanismofthePARPinvolvinginapoptosis　　,PARP,DNAADP-PARP,PARP。PARP,PARP,。,DNAPARP,DNA,DNA,,DNA,,,。PARP,。PARP,DNA,,,,,。,PARP。[][1]　JavierOliverF,GuadalupeR,VeroniqueR,etal.Impor-tanceofpoly(ADP-ribose)polymeraseanditscleavageinapoptosis[J].JBiolChem,1998,273(50):33533-33539.[2]　SimbulanRosenthalCM,RosenthalDS,LyerS,etal.Tran-sientpoly(adp-ribosyl)ationofnuclearproteinsandroleofPARPintheearlystageofapoptosis[J].JBiochem,1998,273(24):13703-13712.[3]　GermainM,AffarEB,DamoursD,etal.Cleavageofauto-modifiedpoly(ADP-ribose)polymeraseduringapoptosis.Evi-denceforinvolvementofcaspase-7[J].JBiolChem,1999,274(40):28379-28384.[4]　BoularesAH,YakovlevAG,IvanovaV,etal.Roleofpoly180S18　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　20026(ADP-ribose)polymerase(PARP)cleavageinapoptosis.Caspase3-resistantPARPmutantincreasesratesofapoptosisintransfectedcells[J].JBiolChem,1999,274(33):22932-22940.[5]　HercegZ,WangZQ.Failureofpoly(ADP-ribose)poly-merasecleavagebycaspasesleadstoinductionofnecrosisansdenhancedapoptosis[J].MolCellBiol,1999,19(6):5124-5133.[6]　DeckerP,BriandJP,deMurciaG,etal.Zincisanessen-tialcofactorforrecognitionoftheDNAbindingdomainofpoly(ADP-ribose)polymerasebyantibodiesinautoimmunerheu-maticandboweldiseases[J].ArthritisRheum,1998,41(5):918-926.[7]　ViatcheslavA,SoldatenkovMD,MarkSmulsonPH.Poly(ADP-ribose)PolymeraseinDNAdamage-responsepathway:implicationsforradiationoncology[J].IntJCancer(RadiatOncolInvest),2000,90(1):59-67.[8]　SmulsonME,SimbulanRosenthalCM,BoularesAH,etal.Rolesofpoly(ADP-ribosyl)ationandPARPinapoptosis,DNArepair,genomicstabilityandfunctionsofp53andE2F-1[J].AdvEnzymeRegul,2000,40183-40215.[9]　RobertsonJD,OrreniusS,ZhivotovskyB.Review:nucleareventsinapoptosis[J].JStructBiol,2000,129(2,3):346-358.[10]BoularesAH,ZoltoskiAJ,ContrerasFJ,etal.RegulationofDNAS1L3endonucleaseactivitybypoly(ADP-ribosyl)ationduringetoposide-inducedapoptosis.Roleofpoly(ADP-ri-bose)polymerase-1cleavageinendonucleaseactivation[J].JBiolChem,2002,277(1):372-378.[11]YakovlevA