A Yeast Model of FUS/TLS-Dependent Cytotoxicity

A Yeast Model of FUS/TLS-Dependent Cytotoxicity

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A Yeast Model of FUS/TLS-Dependent Cytotoxicity

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