Numerical Analysis of Etoposide Induced DNA Breaks 英文参考文献.docVIP

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Numerical Analysis of Etoposide Induced DNA Breaks 英文参考文献.doc

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Numerical Analysis of Etoposide Induced DNA Breaks 英文参考文献

NumericalAnalysisofEtoposideInducedDNABreaks AidaMuslimovic′, SusanneNystro¨m,YueGao,OlaHammarsten* InstituteofBiomedicine,DepartmentofClinicalChemistryandTransfusionMedicine,TheSahlgrenskaAcademyatUniversityofGothenburg,Gothenburg,Sweden Abstract Background:EtoposideisacancerdrugthatinducesstrandbreaksincellularDNAbyinhibitingtopoisomeraseII(topoII) religationofcleavedDNAmolecules.AlthoughDNAcleavagebytopoisomeraseIIalwaysproducestopoisomeraseII-linked DNAdouble-strandbreaks(DSBs),theactionofetoposidealsoresultsinsingle-strandbreaks(SSBs),sincereligationofthe twostrandsareindependentlyinhibitedbyetoposide.Inaddition,recentstudiesindicatethattopoisomeraseII-linkedDSBs remainundetectedunlesstopoisomeraseIIisremovedtoproducefreeDSBs. Methodology/Principal Findings: Toexamineetoposide-induced DNAdamagein moredetailwecomparedtherelative amountofSSBsandDSBs,survivalandH2AXphosphorylationincellstreatedwithetoposideorcalicheamicin,adrugthat producesfreeDSBsandSSBs.Withthiscombinationofmethodswefoundthatonly3%oftheDNAstrandbreaksinduced byetoposidewereDSBs.BycomparingthelevelofDSBs,H2AXphosphorylationandtoxicityinducedbyetoposideand calicheamicin,wefoundthatonly10%ofetoposide-inducedDSBsresultedinhistoneH2AXphosphorylationandtoxicity. TherewasaclosematchbetweentoxicityandhistoneH2AXphosphorylationforcalicheamicinandetoposidesuggesting thatthefewetoposide-inducedDSBsthatactivatedH2AXphosphorylationwereresponsiblefortoxicity. Conclusions/Significance: These results show that only 0.3% of all strand breaks produced by etoposide activate H2AX phosphorylationandsuggeststhatover99%oftheetoposideinducedDNAdamagedoesnotcontributetoitstoxicity. Citation: Muslimovic′ A, Nystro¨m S, Gao Y, Hammarsten O (2009) Numerical Analysis of Etoposide Induced DNA Breaks. PLoS ONE 4(6): e5859. doi:10.1371/ journal.pone.0005859 Editor:BethA.Sullivan,DukeUniversityUnitedStatesofAmerica. ReceivedAugust27,2008;AcceptedApril27,2009;PublishedJune10,2009 Copyright: ?2009Muslimovic′ etal.Thisisanopen-