Ribosomal response to damaged mRNAs

RNA is constantly under attack from endogenous and exogenous damaging agents. Many of these agents are known to alter the chemistry of the nucleobases and hence their functional properties as they are decoded on the ribosome. Furthermore, a number of neurodegenerative diseases have been correlated with accumulation of some of these adducts. Interestingly, a hallmark of neurodegenerative disease is accumulation of misfolded proteins, which in principle can result from increased levels of miscoding. It is also worth noting that certain RNA species can last for days in some tissues, suggesting that any effects of the damage can persist. It is not surprising, then, that a number of quality control processes aimed to clear aberrant mRNAs exist. Our primary focus is oxidative damage to RNA due to its prevalence, but we have also begun to study the effects of alkylation. Initially, we are studying how 8-oxoguanosine, which can mis-pair with adenosine, affects the decoding process using a high-resolution in vitro translation system. We also plan to characterize the fate of oxidized RNAs, and in particular the role of the ribosome in recognizing oxidized mRNAs.