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dc.contributor.authorJu, Shulin
dc.contributor.authorTardiff, Daniel F.
dc.contributor.authorHan, Haesun
dc.contributor.authorDivya, Kanneganti
dc.contributor.authorZhong, Quan
dc.contributor.authorMaquat, Lynne E.
dc.contributor.authorBosco, Daryl A.
dc.contributor.authorHayward, Lawrence J.
dc.contributor.authorBrown, Robert H.
dc.contributor.authorLindquist, Susan
dc.contributor.authorRinge, Dagmar
dc.contributor.authorPetsko, Gregory A.
dc.date.accessioned2011-08-31T19:58:32Z
dc.date.available2011-08-31T19:58:32Z
dc.date.issued2011-04
dc.date.submitted2010-09
dc.identifier.issn1544-9173
dc.identifier.issn1545-7885
dc.identifier.urihttp://hdl.handle.net/1721.1/65580
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.description.sponsorshipFidelity Biosciences (Firm)en_US
dc.description.sponsorshipFidelity Biosciences (Firm) (Research Inititative)en_US
dc.description.sponsorshipALS Therapy Allianceen_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (NIH 1RC1NS06839)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (NIH U01NS05225-03)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (NIH R01NS050557-05)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (NIH 1RC2NS070342-01)en_US
dc.description.sponsorshipPierre L. de Bourgknecht ALS Research Foundationen_US
dc.description.sponsorshipNational Science Foundation (U.S.) (NS614192)en_US
dc.language.isoen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofhttp://dx.doi.org/10.1371/journal.pbio.1001052en_US
dc.rightsCreative Commons Attributionen_US
dc.rights.urihttp://creativecommons.org/licenses/by/2.5/en_US
dc.sourcePLoSen_US
dc.titleA Yeast Model of FUS/TLS-Dependent Cytotoxicityen_US
dc.typeArticleen_US
dc.identifier.citationJu, Shulin et al. “A Yeast Model of FUS/TLS-Dependent Cytotoxicity.” Ed. Jonathan S. Weissman. PLoS Biology 9.4 (2011) : e1001052.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.departmentWhitehead Institute for Biomedical Researchen_US
dc.contributor.approverLindquist, Susan
dc.contributor.mitauthorLindquist, Susan
dc.contributor.mitauthorTardiff, Daniel F.
dc.contributor.mitauthorHan, Haesun
dc.relation.journalPLoS Biologyen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsJu, Shulin; Tardiff, Daniel F.; Han, Haesun; Divya, Kanneganti; Zhong, Quan; Maquat, Lynne E.; Bosco, Daryl A.; Hayward, Lawrence J.; Brown, Robert H.; Lindquist, Susan; Ringe, Dagmar; Petsko, Gregory A.en
dc.identifier.orcidhttps://orcid.org/0000-0003-1307-882X
mit.licensePUBLISHER_CCen_US
mit.metadata.statusComplete


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