Multipotent Genetic Suppression of Retrotransposon-Induced Mutations by Nxf1 through Fine-Tuning of Alternative Splicing 英文参考文献.docVIP

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Multipotent Genetic Suppression of Retrotransposon-Induced Mutations by Nxf1 through Fine-Tuning of Alternative Splicing 英文参考文献.doc

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Multipotent Genetic Suppression of Retrotransposon-Induced Mutations by Nxf1 through Fine-Tuning of Alternative Splicing 英文参考文献

MultipotentGeneticSuppressionofRetrotransposon- InducedMutationsbyNxf1throughFine-Tuningof AlternativeSplicing DorothyConcepcion1,2,3,LisbethFlores-Garc?′a1,2,3,BruceA.Hamilton1,2,3 * 1DepartmentofMedicine,UniversityofCaliforniaSanDiegoSchoolofMedicine,LaJolla,California,UnitedStatesofAmerica,2DepartmentofCellularandMolecular Medicine,UniversityofCaliforniaSanDiegoSchoolofMedicine,LaJolla,California,UnitedStatesofAmerica,3RebeccaandJohnMooresUCSDCancerCenter,University ofCaliforniaSanDiegoSchoolofMedicine,LaJolla,California,UnitedStatesofAmerica Abstract Cellulargeneexpressionmachineryhascoevolvedwithmolecularparasites,suchasvirusesandtransposons,whichrelyon hostcellsfortheirexpressionandreproduction.Wepreviouslyreportedthatawild-derivedalleleofmouseNxf1(Tap),akey component of thehost mRNAnuclear exportmachinery, suppresses twoendogenous retrovirus-induced mutations and showssuggestiveevidenceofpositiveselection.Hereweshowthat Nxf1CAST suppressesaspecificandfrequentclass of intracisternal A particle (IAP)-induced mutations, including Ap3d1mh2J, a model for Hermansky-Pudlak syndrome, and Atcayhes,anorthologousgenemodelforCaymanataxia,amongothers.Themolecularphenotypeofsuppressionincludes ,two-foldincreaseinthelevelofcorrectly-splicedmRNAandadecreaseinmutant-specific,alternatively-processedRNA accumulating from the inserted allele. Insertional mutations involving ETn and LINE elements are not suppressed, demonstratingahighdegreeofspecificitytothissuppressionmechanism.TheseresultsimplicateNxf1insomeinstancesof pre-mRNAprocessing,demonstratetheusefulrangeofNxf1CASTallelesformanipulatingexistingmousemodelsofdisease, andspecificallyimplyalowfunctionalthresholdfortherapeuticbenefitinCaymanataxia. Citation: Concepcion D, Flores-Garc?′a L, Hamilton BA (2009) Multipotent Genetic Suppression of Retrotransposon-Induced Mutations by Nxf1 through Fine- TuningofAlternativeSplicing.PLoSGenet5(5):e1000484.doi:10.1371/journal.pgen.1000484 Editor:WayneN.Frankel,TheJacksonLabo