Translation elongation can control translation initiation on eukaryotic mRNAs

Chu, Dominique; Kazana, Eleanna; Bellanger, Noémie; Singh, Tarun; Tuite, Mick F.; Haar, Tobias von der

doi:10.1002/embj.201385651

Cited by 186 publications

(254 citation statements)

References 56 publications

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“…The first model is based on results from Chu et al (2014) who suggest that slowly elongating ribosomes may restrict initiation by an incoming ribosome; that is, that codon-mediated effects on the translation elongation rate could result in reduced rates of translation initiation. In this model, slow translation of CGA codons closer to the initiation site (in which stalled ribosomes would directly affect the next initiating ribosome) would be more inhibitory than slow translation further from the initiation site; a feedback mechanism of this type would be independent of Asc1 protein and might only operate near the initiation site.…”

Section: Discussionmentioning

confidence: 99%

Asc1, homolog of human RACK1, prevents frameshifting in yeast by ribosomes stalled at CGA codon repeats

Wolf

Grayhack

2015

RNA

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Quality control systems monitor and stop translation at some ribosomal stalls, but it is unknown if halting translation at such stalls actually prevents synthesis of abnormal polypeptides. In yeast, ribosome stalling occurs at Arg CGA codon repeats, with even two consecutive CGA codons able to reduce translation by up to 50%. The conserved eukaryotic Asc1 protein limits translation through internal Arg CGA codon repeats. We show that, in the absence of Asc1 protein, ribosomes continue translating at CGA codons, but undergo substantial frameshifting with dramatically higher levels of frameshifting occurring with additional repeats of CGA codons. Frameshifting depends upon the slow or inefficient decoding of these codons, since frameshifting is suppressed by increased expression of the native tRNA Arg(ICG) that decodes CGA codons by wobble decoding. Moreover, the extent of frameshifting is modulated by the position of the CGA codon repeat relative to the translation start site. Thus, translation fidelity depends upon Asc1-mediated quality control.

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Section: Discussionmentioning

confidence: 99%

Asc1, homolog of human RACK1, prevents frameshifting in yeast by ribosomes stalled at CGA codon repeats

Wolf

Grayhack

2015

RNA

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“…A dual fluorescence reporter plasmid was generated by cloning YFP (Metzger et al 2015) into the vector PTH761 (Chu et al 2013), such that UTR sequences could be inserted upstream of YFP using XmaI and BglII restriction sites (Supplemental Methods). Transcript leaders were cloned between the GPM1 transcription start site and YFP.…”

Section: Testing Uorf Functionsmentioning

confidence: 99%

Conserved non-AUG uORFs revealed by a novel regression analysis of ribosome profiling data

et al. 2017

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Upstream open reading frames (uORFs), located in transcript leaders (5′ UTRs), are potent cis-acting regulators of translation and mRNA turnover. Recent genome-wide ribosome profiling studies suggest that thousands of uORFs initiate with non-AUG start codons. Although intriguing, these non-AUG uORF predictions have been made without statistical control or validation; thus, the importance of these elements remains to be demonstrated. To address this, we took a comparative genomics approach to study AUG and non-AUG uORFs. We mapped transcription leaders in multiple Saccharomyces yeast species and applied a novel machine learning algorithm (uORF-seqr) to ribosome profiling data to identify statistically significant uORFs. We found that AUG and non-AUG uORFs are both frequently found in Saccharomyces yeasts. Although most non-AUG uORFs are found in only one species, hundreds have either conserved sequence or position within Saccharomyces. uORFs initiating with UUG are particularly common and are shared between species at rates similar to that of AUG uORFs. However, non-AUG uORFs are translated less efficiently than AUG-uORFs and are less subject to removal via alternative transcription initiation under normal growth conditions. These results suggest that a subset of non-AUG uORFs may play important roles in regulating gene expression.

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“…For example, as seen previously, efficient translation elongation at the 5′ end of the ORF can lead to increased initiation by faster clearance of ribosomes from the vicinity of the AUG ( Figure 1B) [9]. Alternatively, efficient elongation could lead to faster translation initiation due to effects on mRNP organization ( Figure 1C).…”

mentioning

confidence: 59%

“…This difference could be explained by either an additional decrease in translation initiation, drop-off of elongating ribosomes, or changes in protein stability based on elongation rate. Third, when translation initiation is made inefficient, there is no difference in expression of mRNAs with optimal and non-optimal codons [9]. Finally, similar to decreased translation initiation, non-optimal codons increase the rate of both deadenylation and decapping.…”

mentioning

confidence: 99%

Codon optimality and mRNA decay

Harigaya

Parker

2016

Cell Res

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Recent evidence indicates that codon optimality is a broad determinant of mRNA stability. A study by Radhakrishnan et al. in Cell raises the possibility that the conserved DEAD-box protein Dhh1 underlies the phenomenon.mRNA decay is a critical step in the gene expression process, and the decay rates of individual mRNAs can vary over two orders of magnitude. In eukaryotes, bulk mRNA decay is initiated by deadenylation [1], which allows decapping and 5′ to 3′ degradation but can also lead to 3′ to 5′ degradation [1].Decay rates are inversely related to translation initiation rates, and perturbations that decrease translation initiation enhance both deadenylation and decapping rates. Moreover, specific sequence motifs that are recognized by trans-acting factors, such as microRNAs and RNA-binding proteins, often modulate mRNA stability by controlling translation initiation. This inverse relationship between translation initiation and degradation can be rationalized as the cap and poly(A) tail either being in a translationally competent mRNP or in an alternative nuclease accessible complex.Studies in organisms from E. coli to zebrafish now demonstrate that the "optimality" of an mRNA's codons modulates its stability [2][3][4][5]. The general theme is that "optimal" codons, which are recognized by abundant tRNAs and efficiently translated, are correlated with mRNA stability, whereas "non-optimal" codons, which are recognized by less abundant tRNAs, are correlated with mRNA instability. These correlations show causality since substitutions of

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Translation elongation can control translation initiation on eukaryotic mRNAs

Cited by 186 publications

References 56 publications

Asc1, homolog of human RACK1, prevents frameshifting in yeast by ribosomes stalled at CGA codon repeats

Asc1, homolog of human RACK1, prevents frameshifting in yeast by ribosomes stalled at CGA codon repeats

Conserved non-AUG uORFs revealed by a novel regression analysis of ribosome profiling data

Codon optimality and mRNA decay

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