Replication Pauses of the Wild-Type and Mutant Mitochondrial DNA Polymerase Gamma A Simulation Study 英文参考文献.docVIP

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Replication Pauses of the Wild-Type and Mutant Mitochondrial DNA Polymerase Gamma A Simulation Study 英文参考文献.doc

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Replication Pauses of the Wild-Type and Mutant Mitochondrial DNA Polymerase Gamma A Simulation Study 英文参考文献

ReplicationPausesoftheWild-TypeandMutant MitochondrialDNAPolymeraseGamma:ASimulation Study ZhuoSong1,YangCao2,DavidC.Samuels1* 1CenterforHumanGeneticResearch,VanderbiltUniversityMedicalCenter,Nashville,Tennessee,UnitedStatesofAmerica,2DepartmentofComputerScience,Virginia Tech,Blacksburg,Virginia,UnitedStatesofAmerica Abstract Theactivityofpolymeraseciscomplicated,involvingbothcorrectandincorrectDNApolymerizationevents,exonuclease activity,andthedisassociationofthepolymerase:DNAcomplex.Pausingofpol-cmightincreasethechanceofdeletionand depletionofmitochondrialDNA.Wehavedevelopedastochasticsimulationofpol-cthatmodelsitsactivitiesonthelevelof individualnucleotidesforthereplicationofmtDNA.Thismethodgivesusinsightsintothepausingoftwopol-cvariants:the A467TsubstitutionthatcausesPEOandAlperssyndrome,andtheexonucleasedeficientpol-c(exo2)inprematureaging mousemodels.Tomeasurethepausing,weanalyzedsimulationresultsforthelongesttimeforthepolymerasetomove forwardonenucleotidealongtheDNAstrand.Ourmodeloftheexo2polymerasehadextremelylongpauses,witha30to 300-foldincreaseinthetimerequiredforthelongestsingleforwardstepcomparedtothewild-type,whilethenaturally occurringA467Tvariantshowedatmostadoublinginthelengthofthepausescomparedtothewild-type.Weidentified the cause of these differences in the polymerase pausing time to be the number of disassociations occurring in each forwardstepofthepolymerase. Citation:SongZ,CaoY,SamuelsDC(2011)ReplicationPausesoftheWild-TypeandMutantMitochondrialDNAPolymeraseGamma:ASimulationStudy.PLoS ComputBiol7(11):e1002287.doi:10.1371/journal.pcbi.1002287 Editor:DennisR.Livesay,UNCCharlotte,UnitedStatesofAmerica ReceivedMay6,2011;AcceptedOctober11,2011;PublishedNovember17,2011 Copyright: ? 2011 Song et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalauthorandsourcearecredited. Funding:ThisworkwasfundedbytheNIH/