Functional Connection between Rad51 and PML in Homology-Directed Repair 英文参考文献.docVIP

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Functional Connection between Rad51 and PML in Homology-Directed Repair 英文参考文献.doc

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Functional Connection between Rad51 and PML in Homology-Directed Repair 英文参考文献

FunctionalConnectionbetweenRad51andPMLin Homology-DirectedRepair SergeiBoichuk1,LiangHu1¤a,KathleenMakielski1,PierPaoloPandolfi2,OleV.Gjoerup1*¤b 1CancerVirologyProgram,UniversityofPittsburghCancerInstitute,Pittsburgh,Pennsylvania,UnitedStatesofAmerica,2DepartmentofMedicine,BethIsraelDeaconess CancerCenter,HarvardMedicalSchool,Boston,Massachusetts,UnitedStatesofAmerica Abstract Thepromyelocyticleukemiaprotein(PML)isatumorsuppressorcriticalforformationofnuclearbodies(NBs)performing importantfunctionsintranscription,apoptosis,DNArepairandantiviralresponses.Earlierstudiesdemonstratedthatsimian virus40(SV40)initiatesreplicationnearPMLNBs.HereweshowthatPMLknockdowninhibitsviralreplicationinvivo ,thus indicating a positive role of PML early in infection. SV40 large T antigen (LT) induces DNA damage and, consequently, nuclearfociofthekeyhomologousrecombinationrepairproteinRad51thatcolocalizewithPML.PMLdepletionabrogates LT-inducedRad51foci.LTmaytargetPMLNBstogainaccesstoDNArepairfactorslikeRad51thatarerequiredforviral replication.WehaveusedtheSV40modeltogaininsighttoDNArepaireventsinvolvingPML.Strikingly,eveninnormal cellsdevoidofviraloncoproteins,PMLisfoundtobeinstrumentalforfociofRad51,Mre11andBRCA1,aswellashomology- directedrepairafterdouble-strandbreak(DSB)induction.FollowingLTexpressionorexternalDNAdamage,PMLassociates with Rad51. PML depletion also causes a loss of RPA foci following c-irradiation, suggesting that PML is required for processing of DSBs. Immunofluorescent detection of incorporated BrdU without prior denaturation indicates afailure to generatessDNAfociinPMLknockdowncellsuponc-irradiation.ConsistentwiththelackofRPAandBrdUfoci,c-irradiation failstoinduceChk1activation,whenPMLisdepleted.Takentogether,wehavediscoveredanovelfunctionalconnection between PML and the homologous recombination-mediated repair machinery, which might contribute to PML tumor suppressoractivity. Citation: Boichuk S, Hu L, Makielski K, Pandolfi PP, Gjoerup OV (2011) Functional Conn