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dc.contributor.authorJu, Shulin
dc.contributor.authorTardiff, Daniel F.
dc.contributor.authorHan, Haesun
dc.contributor.authorDivya, Kanneganti
dc.contributor.authorMaquat, Lynne E.
dc.contributor.authorBosco, Daryl A.
dc.contributor.authorHayward, Lawrence J.
dc.contributor.authorLindquist, Susan
dc.contributor.authorWeissman, Jonathan S.
dc.contributor.authorZhong, Quan
dc.contributor.authorBrown, Robert H.
dc.contributor.authorRinge, Dagmar
dc.contributor.authorPetsko, Gregory A.
dc.date.accessioned2011-12-25T15:07:52Z
dc.date.issued2011
dc.identifier.citationJu, Shulin, Daniel F. Tardiff, Haesun Han, Kanneganti Divya, Quan Zhong, Lynne E. Maquat, Daryl A. Bosco, et al. 2011. A Yeast Model of FUS/TLS-Dependent Cytotoxicity. PLoS Biology 9(4): e1001052.en_US
dc.identifier.issn1544-9173en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:5978697
dc.description.abstractFUS/TLS is a nucleic acid binding protein that, when mutated, can cause a subset of familial amyotrophic lateral sclerosis (fALS). Although FUS/TLS is normally located predominantly in the nucleus, the pathogenic mutant forms of FUS/TLS traffic to, and form inclusions in, the cytoplasm of affected spinal motor neurons or glia. Here we report a yeast model of human FUS/TLS expression that recapitulates multiple salient features of the pathology of the disease-causing mutant proteins, including nuclear to cytoplasmic translocation, inclusion formation, and cytotoxicity. Protein domain analysis indicates that the carboxyl-terminus of FUS/TLS, where most of the ALS-associated mutations are clustered, is required but not sufficient for the toxicity of the protein. A genome-wide genetic screen using a yeast over-expression library identified five yeast DNA/ RNA binding proteins, encoded by the yeast genes ECM32, NAM8, SBP1, SKO1, and VHR1, that rescue the toxicity of human FUS/TLS without changing its expression level, cytoplasmic translocation, or inclusion formation. Furthermore, hUPF1, a human homologue of ECM32, also rescues the toxicity of FUS/TLS in this model, validating the yeast model and implicating a possible insufficiency in RNA processing or the RNA quality control machinery in the mechanism of FUS/TLS mediated toxicity. Examination of the effect of FUS/TLS expression on the decay of selected mRNAs in yeast indicates that the nonsense-mediated decay pathway is probably not the major determinant of either toxicity or suppression.en_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi://10.1371/journal.pbio.1001052en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3082520/pdf/en_US
dash.licenseLAA
dc.subjectbiologyen_US
dc.subjectgeneticsen_US
dc.subjectgenetic screensen_US
dc.subjectgenetics of diseaseen_US
dc.subjectmodel organismsen_US
dc.subjectyeast and fungal modelsen_US
dc.subjectSaccaromyces cerevisiaeen_US
dc.subjectmolecular cell biologyen_US
dc.subjectneoroscienceen_US
dc.subjectmedicineen_US
dc.subjectneurologyen_US
dc.subjectmotor neuron diseasesen_US
dc.subjectamyotrophic lateral sclerosisen_US
dc.subjectdementiaen_US
dc.subjectHuntington diseaseen_US
dc.subjectneurodegenerative diseasesen_US
dc.subjectneuromuscular diseasesen_US
dc.subjectneurologyen_US
dc.subjectmotor neuron diseasesen_US
dc.titleA Yeast Model of FUS/TLS-Dependent Cytotoxicityen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalPLoS Biologyen_US
dash.depositing.authorZhong, Quan
dc.date.available2011-12-25T15:07:52Z
dash.affiliation.other100157en_US
dash.affiliation.other100135en_US
dash.affiliation.other100135en_US
dc.identifier.doi10.1371/journal.pbio.1001052*
dash.authorsorderedfalse
dash.contributor.affiliatedPetsko, Gregory
dash.contributor.affiliatedRinge, Dagmar
dash.contributor.affiliatedZhong, Quan


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