Myc Is Required for Activation of the ATM-Dependent Checkpoints in Response to DNA Damage 英文参考文献.docVIP

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Myc Is Required for Activation of the ATM-Dependent Checkpoints in Response to DNA Damage 英文参考文献.doc

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Myc Is Required for Activation of the ATM-Dependent Checkpoints in Response to DNA Damage 英文参考文献

MycIsRequiredforActivationoftheATM-Dependent CheckpointsinResponsetoDNADamage LinaGuerra1.,AmiAlbihn2.,SusannaTronnersjo¨2,QinziYan2,RiccardoGuidi1,BoStenerlo¨w3 ,Torsten Sterzenbach4,ChristineJosenhans4,JamesG.Fox5,DavidB.Schauer5,MonicaThelestam1 ,Lars-Gunnar Larsson2,6,MarieHenriksson2,TeresaFrisan1* 1Departmentsof Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden, 2Departments of Microbiology, Tumor and CellBiology, Karolinska Institutet, Stockholm, Sweden, 3Division of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden, 4Institute for Medical Microbiology and HospitalEpidemiology,HannoverMedicalSchool,Hannover,Germany,5DepartmentofBiologicalEngineering,DivisionofComparativeMedicine,MassachusettsInstitute of Technology, Cambridge, Massachusetts, United States of America, 6Department of Plant Biology and Forest Genetics, Swedish University of Agricultural Sciences, Uppsala,Sweden Abstract Background:TheMYCproteincontrolscellularfunctionssuchasdifferentiation,proliferation,andapoptosis.Inresponseto genotoxicagents,cellsoverexpressingMYCundergoapoptosis.However,theMYC-regulatedeffectorsactingupstreamof themitochondrialapoptoticpathwayarestillunknown. PrincipalFindings:Inthisstudy,wedemonstratethatexpressionofMycisrequiredtoactivatetheAtaxiatelangiectasia mutated (ATM)-dependent DNA damage checkpoint responses in rat cell lines exposed to ionizing radiation (IR) or the bacterialcytolethaldistendingtoxin(CDT).PhosphorylationoftheATMkinaseanditsdownstreameffectors,suchashistone H2AX,wereimpairedinthemycnullcelllineHO15.19,comparedtothemycpositiveTGR-1andHOmyc3cells.Nuclearfoci formationoftheNijmegenBreakageSyndrome(Nbs)1protein,essentialforefficientATMactivation,wasalsoreducedin absence of myc. Knock down of the endogenous levels of MYC by siRNA in the human cell line HCT116 resulted in decreased ATM and CHK2 phosphorylation in response to irradiation. Conversely, cell death induced by UV irradiation, knowntoact