案例生物化學(xué)二repair class zhanglan

GeneticInformationContentsofThis?TypeofDNA?DNARepair? ?SomethingneedsDNADNAofmutation

DNAIsConstantlyChangingthroughtheProcessofMutationlevel NaturalpolymeraseEndogenousDNAROS,ExogenousDNARadiation,Chemical 中的錯堿基配對的錯誤頻率約為10-4-10-聚合酶本身具有校對作用：將不正確插入的核苷酸切除掉，重新加上正確的核苷酸。這樣，每摻入一個核苷酸，發(fā)生錯誤的機會有。EndogenousDNA腺嘌呤的稀有互變異體腺嘌呤的稀有互變異體與胞嘧胸腺嘧啶的稀有互變異構(gòu)體與鳥嘌異異構(gòu)體間自發(fā)地相互變化形成導(dǎo)致下一世代中G－C配對取代A－T配?堿基的環(huán)外氨基有時會自發(fā)脫落，從而胞嘧啶會變成尿嘧?胞嘧啶自發(fā)脫氨基的頻率約為每個細胞每天190?堿基的環(huán)外氨基有時會自發(fā)脫落，從而胞嘧啶會變成尿嘧?胞嘧啶自發(fā)脫氨基的頻率約為每個細胞每天190OO Nitrous DeaminationofcytosinetoMutationGenerationpassedontodaughterDNAs deletionpassedontodaughter堿基修每個哺乳類細胞每天DNA單鏈斷裂發(fā)生的頻率約為5萬次ChemicalTypesChemicalTypesofX-raysandX-raysandγ-raysstrandbreaks;base/sugardestructionUVlightUVlightpyrimidineg紫外線引起的DNA損(cyclobutanering)連成二聚體。260nm Disruptssynthesis;goodforsterilizationofbacteria,badforskinTypesofPhysicalChemical ogs:AlkylatingIntercalatingIntercalating DNAcanIncorporate5-BU ceofNote:changesaG-CpairintoanA-Tpair(G>Aisatransition,C>Tisatransition) EthylmethaneSulfonate(EMS)AlkylatesIntercalatingInsertionsorTheadditionorlossofoneormorebasesinaDNAFrameshiftTheORFofaproteinencodedgeneischangedsothattheC-terminalsideofthemutationiscomple ychanged.ThetranscriptsisdegradedviaNonsense-mediateddecay(NMD)pathwaysifitcontainsprematuretermination(stop)codons(PTCs)EffectsofPoint3rdpositionofa Silent CodingDNAalteredCodingDNAalteredCodingDNAstopCodingDNAstoptruncated

DNAreplication-independentproductionoferroneousTumorTwoStrikeselectivegrowthselectivegrowth

Smallchange,greatsecondroundsecondroundofclonalgrowththatallowsanexpansionofcellnumberOtherdrivergenemutation gene Mut-Drivercodinggenes74-64-~50%chromatin(modification)factors:HIST1H3B,H3F3A,DNMT1,TET1…...Epi-DriverGeneticHeterogeneityofl

Thejoiningofafragmentedchromosometoanon-homologouschromosomethebreakageofachromosomeinwhich eslostduringcell

ExtracopiesofgenesaregeneratedonathebrokenchromosomesegmentisreversedandinsertedbackintothechromosomeIsochromosomescontaineithertwoshortarmsortwolongarms,derivedfromimproperdivisionofthecentromere.ChromosomeNumberAneuploidyAneuploidy:Turnermassive,complexchromosomeNatureMedicine18,1630–1638Genome-widedistributionofsomaticDNACell.2012.148(1-2):DNADNARepairCellularCellularprotectionfromDNANaturalerrors:polymerasebaseselection,proofreading,mismatchrepairEndogenous/exogenousDNAdamage:Baseexcisionrepair,Nucleotideexcisionbination(DNAdoublestrandbreak)polymerasebypass(TranslesionDNAsynthesis)ProofreadingofDNAMostDNApolymerasescontain“proofreading”activity(3’to5’exonuclease)increasesfidelityofreplicationby100X.ProkaryoticMutSbindstoDNAatmismatchsiteMutLrecruitedbyMutLactsasmat betweenMutSandMutHMutHcreatesanick5’totheunmethylatedGATCsiteExonucleasedegradessectionofthestrandcontainingRecognizescorrectstrandbecauseitisunmethylatedGapinDNAisPhotoactivationRepairinPREbondbetweenPhotoreactivation(theenzymeDNApotolyasecapturesenergyfromlightDirectDirectTypesTypesoflesionsrepairedbyOxidativelesions;8-oxo-G,highlymutagenic,mispairswithA,producingGC-->TADeoxyuracil(dU):frommisincorporationofdUordeaminationofdC-->dU,Spontaneousdepurination(esp.G)yieldabasicsitesthatarerepairedbysecondhalfofBERRecognitionofunusualthrough“base out”recognizedbyDNAglycosylaseDNAglycosylaseleision-andhumancellshave8DNAglycosylaseswithdifferentBaseExcisionAPIfadamagedbaseisnotremovedbybaseexcisionbeforeDNAreplicationAfail-safeNucleotideExcisionNucleotideExcisionRecognitionofdoublehelixEnzymescleavedamagedDNAoneithersideofthelesionDNApolymeraseandligasefillinthegap.ModelforEukaryoticNucleotideExcisionRepair:XerodermaPigmentosum（XP） 性干皮病NERenzymeincludingXPA,XPC,XPDandXPFisassociatedwithbinationbinationTranslesionDNAsynthesis:CatalyzedbyaspecializedclassofDNApolymerasesthatsynthesizeDNAdirectilyacrossthesiteofthedamageCharacteristicsCharacteristicsoflesionbypassinresponsetoDNAdamageTheactivationofbinationPost-ReplicationRecA:交換DNA鏈EmergencyDNAEmergencyDNARepairforDoublestrand TheexchangeofhomologousregionsbetweentwoDNADeleteriousmutationswouldn’taccumulateineachbinationgeneratesgeneticdiversity;Criticalforantigenicvariation.Diploideukaryotes:crossingMitoticand binationcanoccurbothduringmitosisandmeiosisOnlymeiotic binationservestheimportantroleofreassortinggenes binationmaybeimportantforrepairofmutationsinoneofapairofsisterchromatidsThecross-strandHollidaystructureisanintermediatein bination(partI)Thecross-strandHollidaystructureisanintermediatein bination(partII) lian RecBCDexonuclease:opensRecBCDRecBCDexonuclease:opens3’Uponrecognitionofχ,the3’to5’nucleaseactivityisattenuated,aweaker5’to3’nucleaseactivityisactivatedontheoppositeTheundegraded3’end

RecA:neededtoformRecA:neededtoformtriple cedstrandbindstooriginalcomplementarystrandoftheinvasivestrandtocreateHollidayHollidayEfficientbranchmigrationrequiresRuvAandEfficientbranchmigrationrequiresRuvAand-resultantstructurebetterabletoundergobranchmigrationandRuvB:formsahexamericringaroundtheDNADNAispumpedthroughtheringusingATPcleavagetodrivethethesynapseis dto RuvC:RuvC:specificallycuttingtheHollidayRuvCisaspecializedresolvethecrossedtheHollidayBreakRepair3’ssDNAGeneGeneTLoxP:34bp:8-bpTLoxP:34bp:8-bpsequenceflankedby13-bpinvertedDeletionofloxP-flankedTissue-SpecificTissuespecific ConditionalKnockoutTissuespecific Silencingthe3rd21#chromosomeusingNature,2013(500):296-clusteredregularlyinterspacedshortpalindromicrepeats(CRISPR)/CRISPR-associated(Cas)systemsNature,2013(495,)GN(20) MovingMcClintock,1983NobelPrizeinMedicineor geneticelementsfoundinIStransposasegeneflankedbyashortinvertedterminalrepeatsTn:transpositionelementsandadditionalshortinvertedterminalrepeatsCutandPasteTranspositionDuplicative like