Methylation of the Tumor Suppressor Protein, BRCA1, Influences Its Transcriptional Cofactor Function 英文参考文献.docVIP

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Methylation of the Tumor Suppressor Protein, BRCA1, Influences Its Transcriptional Cofactor Function 英文参考文献.doc

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Methylation of the Tumor Suppressor Protein, BRCA1, Influences Its Transcriptional Cofactor Function 英文参考文献

MethylationoftheTumorSuppressorProtein,BRCA1, InfluencesItsTranscriptionalCofactorFunction IreneGuendel1,4,LawrenceCarpio1,4,CaitlinPedati1,ArnoldSchwartz2,ChristineTeal3 ,Fatah Kashanchi1,4,KyleneKehn-Hall4* 1Department of Microbiology, Immunology, and Tropical Medicine, The George Washington University Medical Center, Washington, D. C., United States of America, 2DepartmentofPathology,TheGeorgeWashingtonUniversityMedicalCenter,Washington,D.C.,UnitedStatesofAmerica,3BreastCareCenter,TheGeorgeWashington UniversityMedicalCenter,Washington,D.C.,UnitedStatesofAmerica,4DepartmentofMolecularandMicrobiology,NationalCenterforBiodefenseInfectiousDiseases, GeorgeMasonUniversity,Manassas,Virginia,UnitedStatesofAmerica Abstract Background: Approximately half of hereditary breast cancers have mutations in either BRCA1 or BRCA2. BRCA1 is a multifaceted tumor suppressor protein that has implications in processes such as cell cycle, transcription, DNA damage responseandchromatinremodeling.ThismultifunctionalnatureofBRCA1isachievedbyexertingitsmanyeffectsthrough modulation of transcription. Many cellular events are dictated by covalent modification of proteins, an important mechanism in regulating protein and genome function; of which protein methylation is an important posttranslational modificationwithactivatingorrepressiveeffects. Methods/PrincipalFindings:HerewedemonstrateforthefirsttimethatBRCA1ismethylatedbothinbreastcancercelllines andbreastcancertumorsamplesatarginineandlysineresiduesthroughimmunoprecipitationandwesternblotanalysis. ArgininemethylationbyPRMT1wasobservedinvitroandtheregionofBRCA1504–802showntobehighlymethylated. PRMT1wasdetectedincomplexwithBRCA1504–802throughinvitrobindingassaysandco-immunoprecipitatedwithBRCA1. InhibitionofmethylationresultedindecreasedBRCA1methylationandalterationofBRCA1bindingtopromotersinvivoas shownthroughchromatinimmunoprecipitationassays.KnockdownofPRMT1alsoresultedinincreasedBRCA1bindingto particularpromotersinvivo.Finally,followi