Replication Stress Induces Micronuclei Comprising of Aggregated DNA Double-Strand Breaks 英文参考文献.docVIP

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Replication Stress Induces Micronuclei Comprising of Aggregated DNA Double-Strand Breaks 英文参考文献.doc

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Replication Stress Induces Micronuclei Comprising of Aggregated DNA Double-Strand Breaks 英文参考文献

ReplicationStressInducesMicronucleiComprisingof AggregatedDNADouble-StrandBreaks BingXu1,ZhaoliangSun1,ZhaojianLiu1,HaiyangGuo1,QiaoLiu1,HaiyanJiang1,YongxinZou1 ,Yaoqin Gong1,JayA.Tischfield2,ChangshunShao1,2* 1KeyLaboratoryofExperimentalTeratology,MinistryofEducation,andInstituteofMolecularMedicineandGenetics,ShandongUniversitySchoolofMedicine,Jinan, Shandong,China,2DepartmentofGenetics,RutgersUniversity,Piscataway,NewJersey,UnitedStatesofAmerica Abstract Background: Micronuclei (MN) in mammalian cells serve as a reliable biomarker of genomic instability and genotoxic exposure.ElevationofMNiscommonlyobservedincellsbearingintrinsicgenomicinstabilityandinnormalcellsexposedto genotoxicagents.DNAdouble-strandbreaksaremarkedbyphosphorylationofH2AXatserine139(c-H2AX).Onesubclass of MN contains massive and uniform c-H2AX signals. This study tested whether this subclass of MN can be induced by replicationstress. Principal Findings: We observed that a large proportion of MN, from 20% to nearly 50%, showed uniform staining by antibodiesagainstc-H2AX,amarkerofDNAdouble-strandbreaks(DSBs).SuchmicronucleiweredesignatedasMN-c–H2AX (+).WeshowedthatsuchMNcanbeinducedbychemicalsthatareknowntocauseDNAreplicationstressandSphase arrest.Hydroxyurea,aphidicolinandthymidinecouldallsignificantlyinduceMN-c–H2AX(+),whichwereformedduringS phaseandappearedtobederivedfromaggregationofDSBs.MN-c–H2AX(2),MNthatweredevoidofuniformc-H2AX signals,wereinducedtoalesserextentintermsoffoldchange.Paclitaxel,whichinhibitsthedisassemblyofmicrotubules, only induced MN-c–H2AX (2). The frequency of MN-c–H2AX (+), but not that of MN-c–H2AX (2), was also significantly increased in cells that experience S phase prolongation due to depletion of cell cycle regulator CUL4B. Depletion of replicationproteinA1(RPA1)byRNAinterferenceresultedinanelevationofbothMN-c–H2AX(+)andMN-c–H2AX(2). Conclusions/Significance: A subclass of MN, MN-c–H2AX (+), can be preferentially induced by replication stress. Classification of