Kinetics of Translating Ribosomes Determine the Efficiency of Programmed Stop Codon Readthrough

During translation, a stop codon on the mRNA signals the ribosomes to terminate the process. In certain mRNAs, the termination fails due to the recoding of the canonical stop codon, and ribosomes continue translation to generate C-terminally extended protein. This process, termed stop codon readthrough (SCR), regulates several cellular functions. SCR is driven by elements/factors that act immediately downstream of the stop codon. Here, we have analysed the process of SCR using a simple mathematical model to investigate how the kinetics of translating ribosomes influences the efficiency of SCR. Surprisingly, the analysis revealed that the rate of translation inversely regulates the efficiency of SCR. We tested this prediction experimentally in mammalian AGO1 and MTCH2 mRNAs. Reduction in translation either globally by harringtonine or locally by rare codons caused an increase in the efficiency of SCR. Thus, our study has revealed a hitherto unknown mode of regulation of SCR. (c) 2023 Elsevier Ltd. All rights reserved.

Automated summary

This study used a mathematical model to analyze the process of stop codon readthrough (SCR) and found that the translation rate inversely regulates the efficiency of SCR. Experimental results confirmed that reducing translation can increase the efficiency of SCR. This study has revealed a previously unknown mode of regulation for SCR.