Gene-X-ppt(Gene10-基因十)--Chapter16-Outline

Chapter16RepairSystems16.1Introduction•mismatchrepair(MMR)–Atypeofrepairthatcorrectsmispairedbases,typicallyimmediatelyfollowingreplication.–Theprocesspreferentiallycorrectsthesequenceofthedaughterstrandbydistinguishingthedaughterstrandandparentalstrand,sometimesonthebasisoftheirstatesofmethylation.FIGURE01:Thehumangenomehasmanyrepairgenes16.1Introduction•photoreactivation–Arepairmechanismthatusesawhitelight-dependentenzymetosplitcyclobutanepyrimidinedimersformedbyultravioletlight.•excisionrepair–AtypeofrepairsysteminwhichonestrandofDNAisdirectlyexcisedandthenreplacedbyresynthesisusingthecomplementarystrandastemplate.FIGURE02:Excision-repairreplacesdamagedDNA16.1Introduction•baseexcisionrepair(BER)–Apathwayofexcisionrepairthatrecognizesdamagetosinglebases,suchasdeaminiationoralkylation,andeitherrepairsthebasealone(short-patchrepair)orreplaces2–10nucleotides(long-patchrepair).16.1Introduction•nucleotideexcisionrepair(NER)–AnexcisionrepairpathwaythatrecognizesbulkylesionsinDNA(suchasUV-inducedpyrimidinedimers).–NERisdividedintotwomajorsubpathways:transcription-coupledrepair(TC-NER),whichrepairsdamagedinthetranscribedstrandofactivegenes;andglobalgenomerepair(GG-NER),whichrepairsdamageanywhereinthegenome.16.2RepairSystemsCorrectDamagetoDNA•RepairsystemsrecognizeDNAsequencesthatdonotconformtostandardbasepairs.•ExcisionsystemsremoveonestrandofDNAatthesiteofdamageandthenreplaceit.FIGURE03:DeaminationisreversedbyreplacingUwithCFIGURE04:Replicationerrorsintroducemismatchedbasepairs16.2RepairSystemsCorrectDamagetoDNAFIGURE06:MethylationcandistortthestructureofDNAFIGURE07:Depurinationrequiresbasereplacement16.2RepairSystemsCorrectDamagetoDNA•Recombination-repairsystemsuserecombinationtoreplacethedouble-strandedregionthathasbeendamaged.•Allthesesystemsarepronetointroducingerrorsduringtherepairprocess.•Photoreactivationisanonmutagenicrepairsystemthatactsspecificallyonpyrimidinedimers.FIGURE05:Thyminedimersmustberemovedbyexcision16.3ExcisionRepairSystemsinE.coli•TheUvrsystemmakesincisions~12basesapartonbothsidesofdamagedDNA,removestheDNAbetweenthem(excision),andresynthesizesnewDNA.•TranscribedgenesarepreferentiallyrepairedwhenDNAdamageoccurs.FIGURE08:Excisionrepairreplacesadamagedstrand16.4EukaryoticNucleotideExcisionRepairPathways•Xerodermapigmentosum(XP)isahumandiseasecausedbymutationsinanyoneofseveralnucleotideexcisionrepairgenes.•Numerousproteins,includingXPproductsandthetranscriptionfactorTFIIH,areinvolvedineukaryoticnucleotideexcisionrepair.16.4EukaryoticNucleotideExcisionRepairPathwaysFIGURE11:NucleotideexcisionrepairAdaptedfromE.C.Friedberg,etal.,NatureRev.Cancer1(2001):22-23.16.4EukaryoticNucleotideExcisionRepairPathways•Globalgenomerepairrecognizesdamageanywhereinthegenome.•Transcriptionallyactivegenesarepreferentiallyrepairedviatranscription-coupledrepair.•Globalgenomerepairandtranscription-coupledrepairdifferintheirmechanismsofdamagerecognition(XPCvs.RNApolymeraseII).16.4EukaryoticNucleotideExcisionRepairPathways•TFIIHprovidesthelinktoacomplexofrepairenzymes.•MutationsintheXPDcomponentofTFIIHcausethreetypesofhumandiseases.16.5BaseExcisionRepairSystemsRequireGlycosylases•BaseexcisionrepairistriggeredbydirectlyremovingadamagedbasefromDNA.•Baseremovaltriggerstheremovalandreplacementofastretchofpolynucleotides.•Thenatureofthebaseremovalreactiondetermineswhichoftwopathwaysforexcisionrepairisactivated.•Thepolδ/εpathwayreplacesalongpolynucleotidestretch;thepolβpathwayreplacesashortstretch.16.5BaseExcisionRepairSystemsRequireGlycosylases•UracilandalkylatedbasesarerecognizedbyglycosylasesandremoveddirectlyfromDNA.•Glycosylasesandphotolyase(alyase)actbyflippingthebaseoutofthedoublehelix,where,dependingonthereaction,itiseitherremovedormodifiedandreturnedtothehelix.FIGURE12:UracilisremovedfromDNAFIGURE13:Glycosylasesremovebases16.5BaseExcisionRepairSystemsRequireGlycosylasesFIGURE14:Baseremovaltriggersexcisionrepair16.6Error-ProneRepair•DamagedDNAthathasnotbeenrepairedcausesDNApolymeraseIIItostallduringreplication.•DNApolymeraseV(codedbyumuCD)orDNApolymeraseIV(codedbydinB)cansynthesizeacomplementtothedamagedstrand.•TheDNAsynthesizedbyrepairDNApolymerasesoftenhaserrorsinitssequence(error-pronesynthesis).16.7ControllingtheDirectionofMismatchRepair•mutator–Amutationoramutatedgenethatincreasesthebasallevelofmutation.–SuchgenesoftencodeforproteinsthatareinvolvedinrepairingdamagedDNA.•Themutgenescodeforamismatchrepairsystemthatdealswithmismatchedbasepairs.16.7ControllingtheDirectionofMismatchRepair•Thereisabiasintheselectionofwhichstrandtoreplaceatmismatches.•ThestrandlackingmethylationatahemimethylatedGATCCTAGisusuallyreplaced.•ThemismatchrepairsystemisusedtoremoveerrorsinanewlysynthesizedstrandofDNA.AtG-TandC-Tmismatches,theTispreferentiallyremoved.FIGURE17:MethylationdistinguishesDNAstrands16.7ControllingtheDirectionofMismatchRepair•EukaryoticMutS/Lsystemsrepairmismatchesandinsertion/deletionloops.FIGURE19:MutS/MutLrepairreplicationslippages16.8Recombination-RepairSystemsinE.coli•TherecgenesofE.colicodefortheprincipalrecomb