Ccdc94 Protects Cells from Ionizing Radiation by Inhibiting the Expression of p53 英文参考文献.docVIP

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Ccdc94 Protects Cells from Ionizing Radiation by Inhibiting the Expression of p53 英文参考文献.doc

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Ccdc94 Protects Cells from Ionizing Radiation by Inhibiting the Expression of p53 英文参考文献

Ccdc94ProtectsCellsfromIonizingRadiationby InhibitingtheExpressionofp53 ShellySorrells1,SethCarbonneau2,ErikHarrington1,AyeT.Chen3,BridgidHast4,BrettMilash5, UjwalPyati2,MichaelB.Major4,YiZhou3,LeonardI.Zon3,RodneyA.Stewart1,A.ThomasLook2*, CicelyJette1* 1DepartmentofOncologicalSciences,HuntsmanCancerInstitute,UniversityofUtah,SaltLakeCity,Utah,UnitedStatesofAmerica,2DepartmentofPediatricOncology, Dana-FarberCancerInstituteandHarvardMedicalSchool,Boston,Massachusetts,UnitedStatesofAmerica,3DepartmentofHematology/Oncology,Children’sHospital, Boston,Massachusetts,UnitedStatesofAmerica,4DepartmentofCellandDevelopmentalBiology,LinebergerComprehensiveCancerCenter,ChapelHill,NorthCarolina, UnitedStatesofAmerica,5BioinformaticsSharedResource,HuntsmanCancerInstitute,UniversityofUtah,SaltLakeCity,Utah,UnitedStatesofAmerica Abstract DNAdouble-strandbreaks(DSBs)representoneofthemostdeleteriousformsofDNAdamagetoacell.Incancertherapy, induction of cell death by DNA DSBs by ionizing radiation (IR) and certain chemotherapies is thought to mediate the successfuleliminationofcancercells.However,cancercellsoftenevolvetoevadethecytotoxicityinducedbyDNADSBs, thereby forming the basis for treatment resistance. As such, a better understanding of the DSB DNA damage response (DSB–DDR) pathway will facilitate the design of more effective strategies to overcome chemo- and radioresistance. To identifynovelmechanismsthatprotectcellsfromthecytotoxiceffectsofDNADSBs,weperformedaforwardgeneticscreen in zebrafish for recessive mutations that enhance the IR–induced apoptotic response. Here, we describe radiosensitizing mutation7(rs7),whichcausesaseveresensitivityofzebrafishembryonicneuronstoIR–inducedapoptosisandisrequired for the proper development of the central nervous system. The rs7 mutation disrupts the coding sequence of ccdc94 , a highlyconservedgenethathasnopreviouslinkstotheDSB–DDRpathway.WedemonstratethatCcdc94isafunctional memberofthePrp19complexandthatgeneticknockdownofcoremembersofth