Protein synthesis rates and ribosome occupancies reveal determinants of translation elongation rates

Riba, Andrea; Nanni, Noemi Di; Mittal, Nitish; Arhné, Erik; Schmidt, Alexander; Zavolan, Mihaela

doi:10.1073/pnas.1817299116

Cited by 168 publications

(172 citation statements)

References 68 publications

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“…We base our method on a well-established stochastic model for mRNA translation, the totally asymmetric simple exclusion process (TASEP) 11,28 . Over the years, the model has been improved in many ways to better match real translation 29, 30 and has been repeatedly used to interpret experimental data 16,18,24,[31][32][33][34] .…”

Section: Resultsmentioning

confidence: 99%

“…quantification such as RNA-seq with spike-ins 1 and pulsed stable isotope labelling of amino acids 18 . Future developments of NEAR will include these data to obtain a more detailed view on translation dynamics.…”

Section: /29mentioning

confidence: 99%

“…On the one hand, this definition implicitly assumes that ribosome interference is absent. On the other hand, the extent to which ribosome queuing affects translation has been frequently debated (Li, 2015;Diament et al, 2018;Riba et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…However, a large body of work based on mathematical modelling of ribosome dynamics suggests that the protein synthesis rate is negatively affected by increased ribosome density due to ribosome collisions [11][12][13] . To which extent ribosome collisions can be found using ribosome profiling has been an active topic of research [14][15][16][17][18] One of the goals of ribosome profiling is to understand how the elongation rate along the transcript depends on the choice of codons. Codon elongation rates are usually estimated assuming that the ribosome density at codon i is proportional to the ribosome's dwell time on that particular codon 15,16,[19][20][21][22][23][24] ; this assumption follows from the conservation of the ribosome current assuming no ribosome drop-off.…”

Section: Introductionmentioning

confidence: 99%

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Inferring efficiency of translation initiation and elongation from ribosome profiling

Szavits-Nossan

Ciandrini

2019

Preprint

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Ribosome profiles are often interpreted with underlying naive models that are unable to grasp the complexity of the biological process. We develop a Non-Equilibrium Analysis of Ribo-seq (NEAR), and provide unprecedented estimates of translation initiation and elongation efficiencies, emphasising the importance of rating these two stages of translation separately. When examining ribosome profiling in yeast, we observe that translation initiation and elongation are close to their optima, and traffic is minimised at the beginning of the transcript to favour ribosome recruitment. However, we find many sites of congestion along the mRNAs where the probability of ribosome interference can reach 50%. Our analysis excludes unreliable datapoints and discusses biases of the experimental technique; as a result, we conclude that current analyses and definitions of translation efficiency are not adapt to quantitatively asses ribosome interference. *

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Section: Resultsmentioning

confidence: 99%

Section: /29mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inferring efficiency of translation initiation and elongation from ribosome profiling

Szavits-Nossan

Ciandrini

2019

Preprint

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“…Specific sequence motifs can stall translating ribosomes such as select codon pairings (19), or successive proline residues that require the specialized translation factor EF-P for their translation (20). Moreover, these determinants of translation elongation kinetics (21)(22)(23) are selectively placed along mRNA and protein sequences to prevent ribosome traffic jams and overall optimize translation (24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

Inferring translational heterogeneity from ribosome profiling data

Bordignon

Pechmann

2019

Preprint

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Translation of messenger RNAs into proteins by the ribosome is the most important step of protein biosynthesis. Accordingly, translation is tightly controlled and heavily regulated to maintain cellular homeostasis. Ribosome profiling (Ribo-seq) has revolutionized the study of translation by revealing many of its underlying mechanisms. However, equally many aspects of translation remain mysterious, in part also due to persisting challenges in the interpretation of data obtained from Ribo-seq experiments. Here, we show that some of the variability observed in Ribo-seq data has biological origins and reflects programmed heterogeneity of translation. To systematically identify sequences that are differentially translated (DT) across mRNAs beyond what can be attributed to experimental variability, we performed a comparative analysis of Ribo-seq data from Saccharomyces cerevisiae and derived a consensus ribosome density profile that reflects consistent signals in individual experiments. Remarkably, the thus identified DT sequences link to mechanisms known to regulate translation elongation and are enriched in genes important for protein and organelle biosynthesis. Our results thus highlight examples of translational heterogeneity that are encoded in the genomic sequences and tuned to optimizing cellular homeostasis. More generally, our work highlights the power of Ribo-seq to understand the complexities of translation regulation.

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Dominant negative variants and cotranslational assembly of macromolecular complexes

Veitia

2023

BioEssays

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Pathogenic variants occurring in protein‐coding regions underlie human genetic disease through various mechanisms. They can lead to a loss of function (LOF) such as in recessive conditions or in dominant conditions due to haploinsufficiency. Dominant‐negative (DN) effects, counteracting the activity of the normal gene‐product, and gain of function (GOF) are also mechanisms driving dominance. Here, I discuss a few papers on these specific mechanisms. In short, there is accumulating evidence pointing to differences between LOF versus non‐LOF variants (DN and GOF). The latter are thought to have milder effects on protein structure and, as expected, DN variants are enriched at protein interfaces. This tendency to cluster in 3D space can help improve the ability of computational tools to predict the pathogenicity of DN variants, which is currently a challenging issue. More recent results support the hypothesis whereby cotranslational assembly of macromolecular complexes can buffer deleterious consequences of variants that would otherwise lead to DN effects (DNEs). Indeed, subunits the variants of which are responsible for DNEs tend to elude cotranslational assembly, thus poisoning complexes involving wild‐type subunits. The constraints explaining why the buffering of DNEs is not universal require further investigation.

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Protein synthesis rates and ribosome occupancies reveal determinants of translation elongation rates

Cited by 168 publications

References 68 publications

Inferring efficiency of translation initiation and elongation from ribosome profiling

Inferring efficiency of translation initiation and elongation from ribosome profiling

Inferring translational heterogeneity from ribosome profiling data

Dominant negative variants and cotranslational assembly of macromolecular complexes

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