دورية أكاديمية
A yeast model of FUS/TLS-dependent cytotoxicity.
| العنوان: | A yeast model of FUS/TLS-dependent cytotoxicity. |
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| المؤلفون: | Shulin Ju, Daniel F Tardiff, Haesun Han, Kanneganti Divya, Quan Zhong, Lynne E Maquat, Daryl A Bosco, Lawrence J Hayward, Robert H Brown, Susan Lindquist, Dagmar Ringe, Gregory A Petsko |
| المصدر: | PLoS Biology, Vol 9, Iss 4, p e1001052 (2011) |
| بيانات النشر: | Public Library of Science (PLoS), 2011. |
| سنة النشر: | 2011 |
| المجموعة: | LCC:Biology (General) |
| مصطلحات موضوعية: | Biology (General), QH301-705.5 |
| الوصف: | 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. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1544-9173 1545-7885 |
| Relation: | http://europepmc.org/articles/PMC3082520?pdf=render; https://doaj.org/toc/1544-9173; https://doaj.org/toc/1545-7885 |
| DOI: | 10.1371/journal.pbio.1001052 |
| URL الوصول: | https://doaj.org/article/8b86bc019d774b7c96ffcc6d00dbf142 |
| رقم الأكسشن: | edsdoj.8b86bc019d774b7c96ffcc6d00dbf142 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 15449173 15457885 |
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| DOI: | 10.1371/journal.pbio.1001052 |