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A Yeast Model of FUS/TLS-Dependent Cytotoxicity

Research and Teaching Output of the MIT Community

Show simple item record Ju, 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. 2011-08-31T19:58:32Z 2011-08-31T19:58:32Z 2011-04 2010-09
dc.identifier.issn 1544-9173
dc.identifier.issn 1545-7885
dc.description.abstract FUS/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.sponsorship Fidelity Biosciences (Firm) en_US
dc.description.sponsorship Fidelity Biosciences (Firm) (Research Inititative) en_US
dc.description.sponsorship ALS Therapy Alliance en_US
dc.description.sponsorship National Institutes of Health (U.S.) (NIH 1RC1NS06839) en_US
dc.description.sponsorship National Institutes of Health (U.S.) (NIH U01NS05225-03) en_US
dc.description.sponsorship National Institutes of Health (U.S.) (NIH R01NS050557-05) en_US
dc.description.sponsorship National Institutes of Health (U.S.) (NIH 1RC2NS070342-01) en_US
dc.description.sponsorship Pierre L. de Bourgknecht ALS Research Foundation en_US
dc.description.sponsorship National Science Foundation (U.S.) (NS614192) en_US
dc.language.iso en_US
dc.publisher Public Library of Science en_US
dc.relation.isversionof en_US
dc.rights Creative Commons Attribution en_US
dc.rights.uri en_US
dc.source PLoS en_US
dc.title A Yeast Model of FUS/TLS-Dependent Cytotoxicity en_US
dc.type Article en_US
dc.identifier.citation Ju, 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.department Whitehead Institute for Biomedical Research en_US
dc.contributor.department move to dc.description.sponsorship en_US
dc.contributor.department Massachusetts Institute of Technology. Department of Biology en_US
dc.contributor.approver Lindquist, Susan
dc.contributor.mitauthor Lindquist, Susan
dc.contributor.mitauthor Tardiff, Daniel F.
dc.contributor.mitauthor Han, Haesun
dc.relation.journal PLoS Biology en_US
dc.identifier.mitlicense PUBLISHER_CC en_US
dc.eprint.version Final published version en_US
dc.type.uri en_US
eprint.status en_US
dspace.orderedauthors Ju, 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

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