Efficient translation initiation dictates codon usage at gene start

Bentele, Kajetan; Saffert, Paul; Rauscher, Robert; Ignatova, Zoya; Blüthgen, Nils

doi:10.1038/msb.2013.32

Cited by 297 publications

(311 citation statements)

References 46 publications

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“…A genome-wide comparison of the in silico RNA structurome with experimental polysome profiling for allelic variants in hybrid mouse fibroblasts supports these assertions, as alleles with lower in silico-predicted mRNA secondary structure around the transcription start site had greater translation efficiency (defined as the ratio between ribosome-associated mRNA and total mRNA abundance) (37). Ribosome profiling in yeast (86), coupled with a transcriptome-wide sliding window analysis of either in vivo or in vitro structure along transcripts (91), identified low structure in the first window as the strongest regulator of translational efficiency (defined as total amount of protein produced per mRNA), consistent with previous genome-wide in vitro (32,43,57) and in silico structural analyses (5,25,37). In vitro and in vivo structurome studies in systems as disparate as Arabidopsis (22), yeast (91,119), Drosophila, C. elegans (56), mouse and human cell lines (40,106,120), and E. coli (19) have revealed that low structure upstream of the translation start site in comparison with flanking regions is a conserved meta-property ( Table 2).…”

Section: Stability and Degradationsupporting

confidence: 82%

Genome-Wide Analysis of RNA Secondary Structure

Bevilacqua¹,

Ritchey²,

et al. 2016

Annu. Rev. Genet.

204

157

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Single-stranded RNA molecules fold into extraordinarily complicated secondary and tertiary structures as a result of intramolecular base pairing. In vivo, these RNA structures are not static. Instead, they are remodeled in response to changes in the prevailing physicochemical environment of the cell and as a result of intermolecular base pairing and interactions with RNAbinding proteins. Remarkable technical advances now allow us to probe RNA secondary structure at single-nucleotide resolution and genome-wide, both in vitro and in vivo. These data sets provide new glimpses into the RNA universe. Analyses of RNA structuromes in HIV, yeast, Arabidopsis, and mammalian cells and tissues have revealed regulatory effects of RNA structure on messenger RNA (mRNA) polyadenylation, splicing, translation, and turnover. Application of new methods for genome-wide identification of mRNA modifications, particularly methylation and pseudouridylation, has shown that the RNA "epitranscriptome" both influences and is influenced by RNA structure. In this review, we describe newly developed genome-wide RNA structure-probing methods and synthesize the information emerging from their application.

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Section: Stability and Degradationsupporting

confidence: 82%

Genome-Wide Analysis of RNA Secondary Structure

Bevilacqua¹,

Ritchey²,

et al. 2016

Annu. Rev. Genet.

204

157

View full text Add to dashboard Cite

show abstract

“…2) may be supported further by the fine-tuning of the initiation rate via occlusion time due to slow codons [11]: If the translation rates for rare codons are unsaturated, the occlusion time can respond to the changes in the substrate level. Furthermore, secondary mRNA structures near the ribosome binding site is avoided [27] probably because such would reduce the ribosome on-rate, K s [28,29,30]. It is not obvious that slowly translated codons are less likely to form structured mRNA, but altogether it is clear that numerous regards should be solved by the codon usage in the beginning of the mRNA.…”

Section: Summary and Discussionmentioning

confidence: 99%

Control of ribosome traffic by position-dependent choice of synonymous codons

Mitarai¹,

Pedersen²

2013

Phys. Biol.

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Abstract. Messenger RNA encodes a sequence of amino acids by using codons. For most amino acids there are multiple synonymous codons that can encode the amino acid. The translation speed can vary from one codon to another, thus there is room for changing the ribosome speed while keeping the amino acid sequence and hence the resulting protein. Recently, it has been noticed that the choice of the synonymous codon, via the resulting distribution of slow-and fast-translated codons, affects not only on the average speed of one ribosome translating the messenger RNA (mRNA) but also might have an effect on nearby ribosomes by affecting the appearance of "traffic jams" where multiple ribosomes collide and form queues. To test this "context effect" further, we here investigate the effect of the sequence of synonymous codons on the ribosome traffic by using a ribosome traffic model with codon-dependent rates, estimated from experiments. We compare the ribosome traffic on wild type sequences and sequences where the synonymous codons were swapped randomly. By simulating translation of 87 genes, we demonstrate that the wild type sequences, especially those with a high bias in codon usage, tend to have the ability to reduce ribosome collisions, hence optimizing the cellular investment in the translation apparatus. The magnitude of such reduction of the translation time might have a significant impact on the cellular growth rate and thereby have importance for the survival of the species.

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“…When controlling for the mRNA level, a significant negative correlation was observed between CUB as measured in S. cerevisiae and the absolute translational cis ratio, but not the absolute mRNA cis ratio (analysis of covariance [ANCOVA], P = 1.5 3 10 À12 and 0.13, respectively). The presence of mRNA secondary structure in the vicinity of the start codon has also been implicated in reducing translational efficiency (Kudla et al 2009;Robbins-Pianka et al 2010;Bentele et al 2013;Dvir et al 2013;Goodman et al 2013;Shah et al 2013). We found evidence for a positive correlation between species-specific decreases in computationally predicted secondary structure downstream from the start codon and increased translational efficiency (Supplemental Fig.…”

Section: Evolution At Two Levels Of Gene Expressionmentioning

confidence: 99%

Evolution at two levels of gene expression in yeast

2013

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Despite the greater functional importance of protein levels, our knowledge of gene expression evolution is based almost entirely on studies of mRNA levels. In contrast, our understanding of how translational regulation evolves has lagged far behind. Here we have applied ribosome profiling-which measures both global mRNA levels and their translation rates-to two species of Saccharomyces yeast and their interspecific hybrid in order to assess the relative contributions of changes in mRNA abundance and translation to regulatory evolution. We report that both cis-and trans-acting regulatory divergence in translation are abundant, affecting at least 35% of genes. The majority of translational divergence acts to buffer changes in mRNA abundance, suggesting a widespread role for stabilizing selection acting across regulatory levels. Nevertheless, we observe evidence of lineage-specific selection acting on several yeast functional modules, including instances of reinforcing selection acting at both levels of regulation. Finally, we also uncover multiple instances of stop-codon readthrough that are conserved between species. Our analysis reveals the underappreciated complexity of post-transcriptional regulatory divergence and indicates that partitioning the search for the locus of selection into the binary categories of

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Efficient translation initiation dictates codon usage at gene start

Abstract: Rare codons are enriched at gene start in many genomes. Genome analysis and experimental testing show that this enrichment evolved to keep the ribosome binding site free from stable mRNA structures, in order to facilitate efficient translation initiation.

Cited by 297 publications

References 46 publications

Genome-Wide Analysis of RNA Secondary Structure

Genome-Wide Analysis of RNA Secondary Structure

Control of ribosome traffic by position-dependent choice of synonymous codons

Evolution at two levels of gene expression in yeast

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