A role for the ribosome in deciding the fate of damaged RNA (752.10)

Fast and faithful translation of the cellular messenger RNAs is a defining feature of the ribosome and the translation factors. High‐accuracy protein synthesis ensures that errant proteins, which are more prone to misfold, are not made. On aberrant mRNAs, such as truncated ones and those either containing premature or lacking stop codons, a number of ribosome‐based quality control processes ensure that these RNAs are not translated and instead are targeted for degradation. While these mRNA‐surveillance mechanisms have received much attention during the past decade, curiously a different class of aberrant mRNAs has received little study. In particular, chemically‐damaged RNAs pose a significant hurdle to translational fidelity and efficiency. Of particular interest to us is oxidized RNA in the form of 8‐oxoguanine, which has been linked to a number of neurodegenerative diseases. The exact mechanism by which the cell recognizes the aberrant mRNAs and targets them for degradation remains elusive. To this end, we have begun to investigate the effects of oxidation on the decoding process using a high‐resolution‐in‐vitro translation system. Preliminary data suggests that 8‐oxoguanine is detrimental to the decoding process, for which we measure rates of peptide‐bond formation that are 4 to 5 orders of magnitude lower relative to undamaged RNA. We are currently investigating tRNA‐selection steps preceding the final step of peptidyl transfer in an attempt to understand the mechanism by which such a minor change to the nucleobase could have dramatic effects on the decoding process. We are also interested in studying the fate of the oxidized RNAs and the role of the ribosome in this process. Preliminary data is promising and suggests that the ribosome takes advantage of existent quality control processes to target these mRNAs for degradation. Grant Funding Source : NIH