Template-Directed Biopolymerization: Tape-Copying Turing Machines

Sharma, Ajeet K.; Chowdhury, Debashish

doi:10.1142/s1793048012300083

“…It is therefore crucial to be able to accurately measure these rates. The ribosome synthesizes a protein in three steps namely initiation, elongation, and termination [1–3]. Translation is initiated at the start codon of the mRNA transcript by the ribosomal subunits that form a stable translation-initiation complex [4,5].…”

Section: Introductionmentioning

confidence: 99%

A chemical kinetic basis for measuring translation initiation and elongation rates from ribosome profiling data

Sharma

¹

,

Sormanni

²

,

Ahmed

³

et al. 2019

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Analysis methods based on simulations and optimization have been previously developed to estimate relative translation rates from next-generation sequencing data. Translation involves molecules and chemical reactions, hence bioinformatics methods consistent with the laws of chemistry and physics are more likely to produce accurate results. Here, we derive simple equations based on chemical kinetic principles to measure the translation-initiation rate, transcriptome-wide elongation rate, and individual codon translation rates from ribosome profiling experiments. Our methods reproduce the known rates from ribosome profiles generated from detailed simulations of translation. By applying our methods to data from S . cerevisiae and mouse embryonic stem cells, we find that the extracted rates reproduce expected correlations with various molecular properties, and we also find that mouse embryonic stem cells have a global translation speed of 5.2 AA/s, in agreement with previous reports that used other approaches. Our analysis further reveals that a codon can exhibit up to 26-fold variability in its translation rate depending upon its context within a transcript. This broad distribution means that the average translation rate of a codon is not representative of the rate at which most instances of that codon are translated, and it suggests that translational regulation might be used by cells to a greater degree than previously thought.

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“…It is therefore crucial to be able to accurately measure these rates. The synthesis of a protein consists of three sequential phasesinitiation, elongation, and termination [1][2][3]. During the initiation phase ribosome subunits form a stable translation-initiation complex at the start codon of the mRNA transcript [4,5].…”

mentioning

confidence: 99%

A Chemical Kinetic Basis for Measuring Translation Initiation and Elongation Rates from Ribosome Profiling data

Sharma

¹

,

Sormanni²,

Ahmed

³

et al. 2018

Preprint

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Analysis methods based on simulations and optimization have been previously developed to estimate relative translation rates from next-generation sequencing data. Translation involves molecules and chemical reactions; hence, bioinformatics methods consistent with the laws of chemistry and physics are more likely to produce accurate results. Here, we derive simple equations based on chemical kinetic principles to measure the translation-initiation rate, transcriptome-wide elongation rate, and individual codon translation rates from ribosome profiling experiments. Our methods reproduce the known rates from ribosome profiles generated from detailed simulations of translation. Applying our methods to data from S. cerevisiae and mouse embryonic stem cells we find that the extracted rates reproduce expected correlations with various molecular properties. A codon can exhibit up to 26-fold variability in its translation rate depending upon its context within a transcript. This broad distribution means that the average translation rate of a codon is not representative of the rate at which most instances of that codon are translated. We also find that mouse embryonic stem cells have a global translation speed of 5.2 AA/s, is similar to what has been previous reported using another analysis method. This large variability in translation rates suggests that translational regulation might be used by cells to a greater degree than previously thought. ‡ These authors contributed equally to this work.Introduction. Translation-associated rates influence in vivo protein abundance, structure and function. It is therefore crucial to be able to accurately measure these rates. The synthesis of a protein consists of three sequential phasesinitiation, elongation, and termination [1][2][3]. During the initiation phase ribosome subunits form a stable translation-initiation complex at the start codon of the mRNA transcript [4,5]. The ribosome then stochastically moves forward along the transcript one codon at a time during the elongation phase, adding one residue to the nascent chain at each step. The elongation phase is terminated when the ribosome's A-site reaches the stop codon, resulting in release of the fully synthesized protein. The initiation and elongation phases of translation contribute to protein levels inside a cell; indeed, alteration of their rates can cause protein abundance to vary by up to five orders of magnitude [6][7][8], and alter protein structure and function [9]. Termination does not influence the cellular concentration of proteins as it is not a rate limiting step [10]. Therefore, knowledge of translation initiation and codon translation rates are important to understand the regulation of gene expression.Significant efforts have been made to extract these rates from data generated from ribosome profiling experiments [11][12][13][14], a technique that measures the relative ribosome density across transcripts [15]. In a number of methods, the actual rates are not measured but instead a ratio of rates, or other releva...

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“…The first mathematical model of protein synthesis was developed by MacDonald et al (1968) , and since then various similar models and their extensions were proposed to understand the different aspects of mRNA translation ( Garai et al, 2009 ; Sharma and Chowdhury, 2012 ; Ciandrini et al, 2013 ; Margaliot and Tuller, 2013 ). Among these, the totally asymmetric simple exclusion process (TASEP) is a model which incorporates key steps regulating in vivo protein production and is extensively used to stimulate protein synthesis.…”

Section: Quantitative Modeling Of Protein Synthesismentioning

confidence: 99%

“…On the

transcript, a ribosome slides from codon position j to

with rate

. In each of such steps, a ribosome selects cognate aa-tRNA molecule, forms a peptide bond and then moves to the next codon position ( Sharma and Chowdhury, 2011 ; Sharma and Chowdhury, 2012 ) Note that multiple ribosomes simultaneously move on a single transcript where each of them synthesizes a separate copy of protein. Therefore, due to mutual exclusion, a ribosome cannot move to the next codon if its passage is blocked by another downstream ribosome.…”

Section: Quantitative Modeling Of Protein Synthesismentioning

confidence: 99%

Quantitative Modeling of Protein Synthesis Using Ribosome Profiling Data

Yadav

¹

,

Irshad

²

,

Kumar

³

et al. 2021

Front. Mol. Biosci.

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Quantitative prediction on protein synthesis requires accurate translation initiation and codon translation rates. Ribosome profiling data, which provide steady-state distribution of relative ribosome occupancies along a transcript, can be used to extract these rate parameters. Various methods have been developed in the past few years to measure translation-initiation and codon translation rates from ribosome profiling data. In the review, we provide a detailed analysis of the key methods employed to extract the translation rate parameters from ribosome profiling data. We further discuss how these approaches were used to decipher the role of various structural and sequence-based features of mRNA molecules in the regulation of gene expression. The utilization of these accurate rate parameters in computational modeling of protein synthesis may provide new insights into the kinetic control of the process of gene expression.

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Template-Directed Biopolymerization: Tape-Copying Turing Machines

Cited by 14 publications

References 187 publications

A chemical kinetic basis for measuring translation initiation and elongation rates from ribosome profiling data

A chemical kinetic basis for measuring translation initiation and elongation rates from ribosome profiling data

A Chemical Kinetic Basis for Measuring Translation Initiation and Elongation Rates from Ribosome Profiling data

Quantitative Modeling of Protein Synthesis Using Ribosome Profiling Data

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