An E2F1-Mediated DNA Damage Response Contributes to the Replication of Human Cytomegalovirus 英文参考文献.docVIP

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An E2F1-Mediated DNA Damage Response Contributes to the Replication of Human Cytomegalovirus 英文参考文献.doc

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An E2F1-Mediated DNA Damage Response Contributes to the Replication of Human Cytomegalovirus 英文参考文献

AnE2F1-MediatedDNADamageResponseContributes totheReplicationofHumanCytomegalovirus XiaofeiE1,2.,MaryT.Pickering1.,MichelleDebatis1,JonathanCastillo1,2,AlexanderLagadinos1,2 ,Shixia Wang2,3,ShanLu2,3,TimothyF.Kowalik1,2 * 1DepartmentofMicrobiologyandPhysiologicalSystems,UniversityofMassachusettsMedicalSchool,Worcester,Massachusetts,UnitedStatesofAmerica,2Programin Immunology and Virology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America, 3Laboratory of Nucleic Acid Vaccines, DepartmentofMedicine,UniversityofMassachusettsMedicalSchool,Worcester,Massachusetts,UnitedStatesofAmerica Abstract DNA damage resulting from intrinsic or extrinsic sources activates DNA damage responses (DDRs) centered on protein kinase signaling cascades. The usual consequences of inducing DDRs include the activation of cell cycle checkpoints togetherwithrepairofthedamagedDNAorinductionofapoptosis.ManyDNAviruseselicithostDDRsduringinfectionand some viruses require the DDR for efficient replication. However, the mechanism by which DDRs are activated by viral infection is poorly understood. Human cytomegalovirus (HCMV) infection induces a DDR centered on the activation of ataxia telangiectasia mutated (ATM) protein kinase. Here we show that HCMV replication is compromised in cells with inactivated or depleted ATM and that ATM is essential for the host DDR early during infection. Likewise, a downstream targetofATMphosphorylation,H2AX,alsocontributestoviralreplication.TheATM-dependentDDRisdetectedasdiscrete, nuclearcH2AXfociearlyininfectionandcanbeactivatedbyIEproteins.By24hpi,cH2AXisobservedprimarilyinHCMV DNA replication compartments. We identified a role for the E2F1 transcription factor in mediating this DDR and viral replication. E2F1, but not E2F2 or E2F3, promotes the accumulation of cH2AX during HCMV infection or IE protein expression.Moreover,E2F1expression,butnottheexpressionofE2F2orE2F3,isrequiredforefficientHCMVreplication. Theseresultsreve