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Nature. 2018 Jul;559(7712):130-134. doi: 10.1038/s41586-018-0258-0. Epub 2018 Jun 27.

The helicase Ded1p controls use of near-cognate translation initiation codons in 5' UTRs.

Author information

1
Center for RNA Science and Therapeutics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
2
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
3
Howard Hughes Medical Institute Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
4
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
5
Howard Hughes Medical Institute California Institute for Quantitative Biomedical Research, San Francisco, CA, USA.
6
Department of Molecular and Cell Biology, University of California, Berkeley, CA, USA.
7
Center for RNA Science and Therapeutics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA. exj13@case.edu.
8
Department of Physics, Case Western Reserve University, Cleveland, OH, USA. exj13@case.edu.

Abstract

The conserved and essential DEAD-box RNA helicase Ded1p from yeast and its mammalian orthologue DDX3 are critical for the initiation of translation1. Mutations in DDX3 are linked to tumorigenesis2-4 and intellectual disability5, and the enzyme is targeted by a range of viruses6. How Ded1p and its orthologues engage RNAs during the initiation of translation is unknown. Here we show, by integrating transcriptome-wide analyses of translation, RNA structure and Ded1p-RNA binding, that the effects of Ded1p on the initiation of translation are connected to near-cognate initiation codons in 5' untranslated regions. Ded1p associates with the translation pre-initiation complex at the mRNA entry channel and repressing the activity of Ded1p leads to the accumulation of RNA structure in 5' untranslated regions, the initiation of translation from near-cognate start codons immediately upstream of these structures and decreased protein synthesis from the corresponding main open reading frames. The data reveal a program for the regulation of translation that links Ded1p, the activation of near-cognate start codons and mRNA structure. This program has a role in meiosis, in which a marked decrease in the levels of Ded1p is accompanied by the activation of the alternative translation initiation sites that are seen when the activity of Ded1p is repressed. Our observations indicate that Ded1p affects translation initiation by controlling the use of near-cognate initiation codons that are proximal to mRNA structure in 5' untranslated regions.

PMID:
29950728
PMCID:
PMC6226265
DOI:
10.1038/s41586-018-0258-0
[Indexed for MEDLINE]
Free PMC Article

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