Ref HAL: hal-01585251_v1
Ref Arxiv: 1708.07678
DOI: 10.1103/PhysRevLett.120.128101
WoS: 000427804000009
Ref. & Cit.: NASA ADS
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14 Citations
Résumé:

One of the greatest challenges in biophysical models of translation is to identify coding sequences features that affect the rate of translation and therefore the overall protein production in the cell. We propose an analytic method to solve a translation model based on the inhomogeneous totally asymmetric simple exclusion process, which allow us to unveil simple design principles of nucleotide sequences determining protein production rates. Our solution shows an excellent agreement when compared to numerical genome-wide simulations of S. cerevisiae transcript sequences and predicts that the first 10 codons, together with the value of the initiation rate, are the main determinants of protein production rate. Finally, we interpret the obtained analytic results based on the evolutionary role of codons' choice for regulating translation rates and ribosome densities.

Commentaires: 5 pages, 3 figures, Supplemental Material (3 pages)

Ref HAL: hal-01939053_v1
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Résumé:

Gene expression and cellular physiology are deeply connected. In this talk I present a few ideas on how I imagine to relate those processes with a mathematical model.

Ref HAL: hal-01939004_v1
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Résumé:

Proteins are the basis of cellular functions, yet key parameters regulating protein synthesis remain elusive. Understanding the fine mechanisms of this regulation is a major goal of molecular and systems biology, and this knowledge will support many “synthetic biological” applications.We have the ambitious goal of providing a comprehensive modeling framework of one of the last steps of protein synthesis, namely mRNA translation. In this presentation I will focus on translation initiation and elongation, which relative role is highly debated in the literature (is the ribosome recruitment or the codon bias determining the expression of a gene?). Here I will explain how the transcript efficiency can be dictated by ribosome abundances, codon usage and transcript length. We propose an approach based on the standard exclusion process, a prototypic lattice gas model. This mathematical framework considers long-range dynamical effects often neglected in standard translation models.The model is compared to experimental ribosome density and gene expression data, which are well reproduced qualitatively and quantitatively. The proposed mathematical framework also describes the origins of the well-known and yet not understood relation between transcript efficiency and its length. We also speculate on the role of transcript length in the competition for ribosomes among different mRNAs.

Ref HAL: hal-02060317_v1
PMID 27407108
DOI: 10.1093/nar/gkw630
WoS: 000388016900022
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10 Citations
Résumé:

tRNA gene copy number is a primary determinant of tRNA abundance and therefore the rate at which each tRNA delivers amino acids to the ribosome during translation. Low-abundance tRNAs decode rare codons slowly, but it is unclear which genes might be subject to tRNA-mediated regulation of expression. Here, those mRNA targets were identified via global simulation of translation. In-silico mRNA translation rates were compared for each mRNA in both wild-type and a [Formula: see text] sup70-65 mutant, which exhibits a pseudohyphal growth phenotype and a 75% slower CAG codon translation rate. Of 4900 CAG-containing mRNAs, 300 showed significantly reduced in silico translation rates in a simulated tRNA mutant. Quantitative immunoassay confirmed that the reduced translation rates of sensitive mRNAs were [Formula: see text] concentration-dependent. Translation simulations showed that reduced [Formula: see text] concentrations triggered ribosome queues, which dissipated at reduced translation initiation rates. To validate this prediction experimentally, constitutive gcn2 kinase mutants were used to reduce in vivo translation initiation rates. This repaired the relative translational rate defect of target mRNAs in the sup70-65 background, and ameliorated sup70-65 pseudohyphal growth phenotypes. We thus validate global simulation of translation as a new tool to identify mRNA targets of tRNA-specific gene regulation.

Ref HAL: hal-01939095_v1
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Résumé:

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