Evolutionary Constraint Helps Unmask a Splicing Regulatory Region in BRCA1 Exon 11 英文参考文献.docVIP

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Evolutionary Constraint Helps Unmask a Splicing Regulatory Region in BRCA1 Exon 11 英文参考文献.doc

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Evolutionary Constraint Helps Unmask a Splicing Regulatory Region in BRCA1 Exon 11 英文参考文献

EvolutionaryConstraintHelpsUnmaskaSplicing RegulatoryRegioninBRCA1Exon11 MichelaRaponi1.,AndrewG.L.Douglas1,2.,ClaudiaTammaro1,DavidI.Wilson1,DianaBaralle1,2* 1HumanDevelopmentandHealth,FacultyofMedicine,UniversityofSouthampton,Southampton,UnitedKingdom,2WessexClinicalGeneticsService,Southampton UniversityHospitalsNHSTrust,Southampton,UnitedKingdom Abstract Background:Alternativesplicingacrossexon11producesseveralBRCA1isoforms.Theirproportionvariesduringthecell cycle, between tissues and in cancer suggesting functional importance of BRCA1 splicing regulation around this exon. Although the regulatory elements driving exon 11 splicing have never been identified, a selective constraint against synonymoussubstitutions(silentnucleotidevariationsthatdonotaltertheaminoacidresiduesequence)inacriticalregion ofBRCA1exon11hasbeenreportedtobeassociatedwiththenecessitytomaintainregulatorysequences. Methodology/PrincipalFindings:Herewehavedesignedaspecificminigenetoinvestigatethepossibilitythatthisbiasin synonymouscodonusagereflectstheneedtopreservetheBRCA1alternativesplicingprogram.Wereportthatin-frame deletionsandtranslationallysilentnucleotidesubstitutionsinthecriticalregionaffectsplicingregulationofBRCA1exon11. Conclusions/Significance: Using ahybridminigeneapproach, wehaveexperimentally validated thehypothesis that the needtomaintaincorrectalternativesplicingisaselectivepressureagainsttranslationallysilentsequencevariationsinthe criticalregionofBRCA1exon11.Identificationofthetrans-actingfactorsinvolvedinregulatingexon11alternativesplicing willbeimportantinunderstandingBRCA1-associatedtumorigenesis. Citation:RaponiM,DouglasAGL,TammaroC,WilsonDI,BaralleD(2012)EvolutionaryConstraintHelpsUnmaskaSplicingRegulatoryRegioninBRCA1Exon 11.PLoSONE7(5):e37255.doi:10.1371/journal.pone.0037255 Editor:LudmilaProkunina-Olsson,NationalCancerInstitute,NationalInstitutesofHealth,UnitedStatesofAmerica ReceivedJanuary16,2012;AcceptedApril18,2012;PublishedMay16,2012 Copyright: ? 2012 Raponi et