An Active Role for the Ribosome in Determining the Fate of Oxidized mRNA

• Oxidized mRNA is detrimental for tRNA selection on the ribosome
• 8-oxoG stalls translation regardless of its position within the codon
• In the absence of no-go decay factors, 8-oxoG-containing mRNAs accumulate in vivo
• mRNA surveillance mechanisms have evolved to deal with damaged mRNA

SummaryChemical damage to RNA affects its functional properties and thus may pose a significant hurdle to the translational apparatus; however, the effects of damaged mRNA on the speed and accuracy of the decoding process and their interplay with quality-control processes are not known. Here, we systematically explore the effects of oxidative damage on the decoding process using a well-defined bacterial in vitro translation system. We find that the oxidative lesion 8-oxoguanosine (8-oxoG) reduces the rate of peptide-bond formation by more than three orders of magnitude independent of its position within the codon. Interestingly, 8-oxoG had little effect on the fidelity of the selection process, suggesting that the modification stalls the translational machinery. Consistent with these findings, 8-oxoG mRNAs were observed to accumulate and associate with polyribosomes in yeast strains in which no-go decay is compromised. Our data provide compelling evidence that mRNA-surveillance mechanisms have evolved to cope with damaged mRNA.

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