A Yeast Model of FUS/TLS-Dependent Cytotoxicity

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A Yeast Model of FUS/TLS-Dependent Cytotoxicity

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dc.contributor.author Ju, Shulin
dc.contributor.author Tardiff, Daniel F.
dc.contributor.author Han, Haesun
dc.contributor.author Divya, Kanneganti
dc.contributor.author Maquat, Lynne E.
dc.contributor.author Bosco, Daryl A.
dc.contributor.author Hayward, Lawrence J.
dc.contributor.author Lindquist, Susan
dc.contributor.author Weissman, Jonathan S.
dc.contributor.author Zhong, Quan
dc.contributor.author Brown, Robert H.
dc.contributor.author Ringe, Dagmar
dc.contributor.author Petsko, Gregory A.
dc.date.accessioned 2011-12-25T15:07:52Z
dc.date.issued 2011
dc.identifier.citation Ju, 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.issn 1544-9173 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:5978697
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.language.iso en_US en_US
dc.publisher Public Library of Science en_US
dc.relation.isversionof doi://10.1371/journal.pbio.1001052 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3082520/pdf/ en_US
dash.license LAA
dc.subject biology en_US
dc.subject genetics en_US
dc.subject genetic screens en_US
dc.subject genetics of disease en_US
dc.subject model organisms en_US
dc.subject yeast and fungal models en_US
dc.subject Saccaromyces cerevisiae en_US
dc.subject molecular cell biology en_US
dc.subject neoroscience en_US
dc.subject medicine en_US
dc.subject neurology en_US
dc.subject motor neuron diseases en_US
dc.subject amyotrophic lateral sclerosis en_US
dc.subject dementia en_US
dc.subject Huntington disease en_US
dc.subject neurodegenerative diseases en_US
dc.subject neuromuscular diseases en_US
dc.subject neurology en_US
dc.subject motor neuron diseases en_US
dc.title A Yeast Model of FUS/TLS-Dependent Cytotoxicity en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal PLoS Biology en_US
dash.depositing.author Zhong, Quan
dc.date.available 2011-12-25T15:07:52Z
dash.affiliation.other 100157 en_US
dash.affiliation.other 100135 en_US
dash.affiliation.other 100135 en_US

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