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WelcometoMyMolecularBiologyClassMolecularBiologyoftheGene,5/E---Watsonetal.(2004)PartI:ChemistryandGeneticsPartII:MaintenanceoftheGenomePartIII:ExpressionoftheGenomePartIV:RegulationPartV:Methods3/22/05PartII:MaintenanceoftheGenomeDedicatedtothestructureofDNAandtheprocessesthatpropagate,maintainandalteritfromonecellgenerationtothenextCh6:ThestructuresofDNAandRNACh7:Chromosomes,chromatinsandthenucleosomeCh8:ThereplicationofDNACh9:ThemutabilityandrepairofDNACh10:HomologousrecombinationatthemolecularlevelCh11:Site-specificrecombinationandtranspositionofDNA3/22/05TheconsequenceofhighratesofmutationMutationingermline(生殖细胞)woulddestroythespeciesMutationinsoma(体细胞)woulddestroytheindividual.MaintenanceofthecorrectnessoftheDNAsequenceisdefinitelycrucialforlivingorganisms.Keepingtheerrorrateaslowas10-10(page191)isveryexpensive.Buildupaseriousattitudetoscience!!!IabsolutelydonotagreewithWastonetal.atthepointsdescribed3rd&4thparagraphsonpage2351.Whatarethemorereasonableexplanationsforthe10-10mutationfrequencyinlivingorganisms?2.Whataretheevidencesthatsuchalowmutationratecandrivetheevolvementofanewspeciesifthecellchangesareknownharmful?ListeningtonatureMutation(突变)isnaturallyavoidedbyrepairoftheerrorsanddamages,suggestingitisgenerallynotwelcomeinlivingorganisms.Recombination(重组)isgoodandnaturallypromoted;itisresponsiblefordiversityinsideofspecies.Transposition(转座)isdifferentfrommutationandrecombinationbecause(1)producingmechanismisdifferent;(2)nomechanismtocorrectit;(3)existinginnatureinawell-controlledmanner(10-5).Notrepairedbutcontrolled.CHAPTER9:ThemutabilityandrepairofDNA•MolecularBiologyCourse1.Replicationerrorsandtheirrepair2.DNAdamage3.RepairofDNAdamage3teachinghoursTwoimportantsourcesformutation(unavoidable)InaccuracyinDNAreplication(10-7isnotaccurateenough)Errors(错误)Chemicaldamagetothegeneticmaterial(environment)Lesions(损害,伤害arosefromspontaneousdamage)Damage(损害,伤害causedbychemicalagentsandradiationTorepairanerrorordamageFirst,DetecttheerrorsSecond,Mend/repairtheerrorsorlesionsinawaytorestoretheoriginalDNAsequence.Questionstobeaddressed1.HowistheDNAmendedrapidlyenoughtopreventerrorsfrombecomingsetinthegeneticmaterialasmutation2.Howdoesthecelldistinguishtheparentalstrandfromthedaughterstrandinrepairingreplicationerrors3.HowdoesthecellrestoretheproperDNAsequencewhentheoriginalsequencecannolongerberead?4.Howdoesthecelldealwithlesionsthatblockreplication?Topic1:ReplicationerrorsandtheirrepairCHAPTER9ThemutabilityandrepairofDNA1.Howthereplicationerrorsareresulted?Thenatureofthereplicationerrorsismismatch.2.Howmismatchesarerecognizedandcorrectlyrepair?ThenatureofmutationsPointmutations:1.Transitions(pyrimidinetopyrimidine,purinetopurine)2.Transversions(pyrimidinetopurine,purinetopyrimidine)ReplicationerrorsandreplicationInsertionsDeletionsGrossrearrangementofchromosome.Thesemutationsmightbecausedbyinsertionbytransposonorbyaberrantactionofcellularrecombinationprocesses.Rateofspontaneousmutationatanygivensiteonchromosomalrangesfrom10-6to10-11perroundofDNAreplication,withsomesitesbeing“hotspot”.Mutation-pronesequenceinhumangenomearerepeatsofsimpledi-,tri-ortetranucleotidesequences,knownasDNAmicrosatellites(微卫星DNA).Thesesequences(1)areimportantinhumangeneticsanddisease,(2)hardtobecopiedaccuratelyandhighlypolymorphicinthepopulation.1.Howthereplicationerrorsareresulted?Eachbaseshasitspreferredtautomericform(Ch6)Thestrictnessoftherulesfor“Waston-Crick”pairingderivesfromthecomplementaritybothofshapeandofhydrogenbondingpropertiesbetweenadenineandthymineandbetweenguanineandcytosine.SomereplicationerrorsescapeproofreadingThe3’-5’exonucleaseactivityofreplisomeonlyimprovesthefidelityofDNAreplicationbyafactorof100-fold.Themisincorporatednucleotideneedstobedetectedandreplaced,otherwiseitwillcausemutation(Fig.9-2).ReplicationerrorsandreplicationFigure9-2GenerationofMutation2.Howthereplicationerrorsarerepaired?MismatchrepairremoveserrorsthatescapeproofreadingIncreasetheaccuracyofDNAsynthesisfor2-3ordersofmagnitudes.Twochallenges:(1)rapidlyfindthemismatches/mispairs,(2)AccuratelycorrectthemismatchReplicationerrorsandreplicationTalkingaboutthestoryofE.colirepairsystemMutSscanstheDNA,recognizingthemismatchfromthedistortiontheycauseintheDNAbackboneMutSembracesthemismatch-containingDNA,inducingapronouncedkinkintheDNAandaconformationalchangeinMutSitselfFigure9-4CrystalstructureofMutSMutSisadimer.Onemonomerinteractswiththemismatchspecifically,andtheothernonspecifically.DNAiskinkedMutS-mismatch-containingDNAcomplexrecruitsMutL,MutLactivatesMutH,anenzymecausinganincisionornickononestrandnearthesiteofthemismatch.Nickingisfollowedbythespecifichelicase(why?)(UrvD)andoneofthreeexonucleases(why?).DNApolymeraseIIIHelicaseExonuclease,Detail1:HowdoestheE.colimismatchrepairsystemknowwhichofthetwomismatchednucleotidetoreplace?ThenewlysynthesizedstrandisnotmethylatedbyDammethylaseinafewminutesafterthesynthesis.Figure9-5Detail2:DifferentexonucleasesareusedtoremovessDNAbetweenthenickcreatedbyMutHandthemismatch.Figure9-6Eukaryoticcellsalsorepairmismat
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