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 |
dc.identifier.doi | 10.1371/journal.pbio.1001052 | * |
dash.authorsordered | false | |
dash.contributor.affiliated | Petsko, Gregory | |
dash.contributor.affiliated | Ringe, Dagmar | |
dash.contributor.affiliated | Zhong, Quan | |