mRNA Translation Stalling in Single-Codon Resolution Monte-Carlo Ribosome Flow Model Simulations

KatrinSchröder

Goethe University

"mRNA Translation Stalling in Single-Codon Resolution Monte-Carlo Ribosome Flow Model Simulations"

Ribosomal stalling during translation of mRNA can result for example from oxidative conditions surrounding the site of translation. It impacts the cellular protein production machinery and therefore decrease cell proliferation. Accordingly, the rate of protein synthesis (R) can be considered as a hallmark of ribosomal stalling. In vivo experiments can determine protein content of a cell and differences in ribosomal density for different stalling scenarios. We employ the Ribosome Flow Model (RFM) coupled with Monte Carlo simulations to quantitatively establish the implications of three stalling patterns motivated by biological processes: We consider (1) the overall frequency of stalling sides as defined by harmful mRNA modification, (2) the degree of the reduction of the translocation rate λ reflecting the severity of mRNA transcriptional impairments, as well as (3) the effect of clustering, chain and gap impairments, as well as cluster locality of these anomalies. Each of these stalling patterns impacts protein synthesis rate and ribosomal density differently. We show how quantitative prediction of the impact of each and combinations of these patterns can be used as to study and predict mRNA stalling. Major findings of our analysis are, that for a given severity of mRNA damage, the equilibrium rate of protein synthesis R* does not depend on impairment locality, and is not related to the ribosomal density. In contrast, ribosomal density is strongly dependent on the locality of impairment clustering.
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