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GIGYF2 and 4EHP Inhibit Translation Initiation of Defective Messenger RNAs to Assist Ribosome-Associated Quality Control.
Hickey, Kelsey L; Dickson, Kimberley; Cogan, J Zachery; Replogle, Joseph M; Schoof, Michael; D'Orazio, Karole N; Sinha, Niladri K; Hussmann, Jeffrey A; Jost, Marco; Frost, Adam; Green, Rachel; Weissman, Jonathan S; Kostova, Kamena K.
Afiliación
  • Hickey KL; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Dickson K; Department of Biology, Lawerence University, Appleton, WI 54911, USA.
  • Cogan JZ; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Replogle JM; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Schoof M; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
  • D'Orazio KN; Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.
  • Sinha NK; Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.
  • Hussmann JA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Jost M; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94158, USA.
  • Frost A; California Institute for Quantitative Biomedical Research, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
  • Green R; Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA; Howard Hughes Medical Institute, Carnegie Institution for Science, Baltimore, MD 21218, USA.
  • Weissman JS; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; California Institute for Quantitative Biomedical Research, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, Carnegie Instit
  • Kostova KK; Department of Embryology, Carnegie Institution for Science, Baltimore, MD 21218, USA. Electronic address: kostova@carnegiescience.edu.
Mol Cell ; 79(6): 950-962.e6, 2020 09 17.
Article en En | MEDLINE | ID: mdl-32726578
ABSTRACT
Ribosome-associated quality control (RQC) pathways protect cells from toxicity caused by incomplete protein products resulting from translation of damaged or problematic mRNAs. Extensive work in yeast has identified highly conserved mechanisms that lead to degradation of faulty mRNA and partially synthesized polypeptides. Here we used CRISPR-Cas9-based screening to search for additional RQC strategies in mammals. We found that failed translation leads to specific inhibition of translation initiation on that message. This negative feedback loop is mediated by two translation inhibitors, GIGYF2 and 4EHP. Model substrates and growth-based assays established that inhibition of additional rounds of translation acts in concert with known RQC pathways to prevent buildup of toxic proteins. Inability to block translation of faulty mRNAs and subsequent accumulation of partially synthesized polypeptides could explain the neurodevelopmental and neuropsychiatric disorders observed in mice and humans with compromised GIGYF2 function.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Iniciación de la Cadena Peptídica Traduccional / Ribosomas / Proteínas Portadoras / Factor 4E Eucariótico de Iniciación Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Iniciación de la Cadena Peptídica Traduccional / Ribosomas / Proteínas Portadoras / Factor 4E Eucariótico de Iniciación Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: Mol Cell Asunto de la revista: BIOLOGIA MOLECULAR Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos