Role of the Ribosome in Damaged-RNA Response
The Zaher lab is interested in the functional role of RNA during the process of translation. Our long-term goal is to investigate the mechanism of ribosome function and to understand how other cellular factors and alterations to the RNA modulate its function. We are interested in understanding the molecular mechanics of the translational machinery and how the ribosome reads cues to modulate its activity. It is clear that the ribosome is subject to multiple levels of regulation at each step that affect a diverse range of biological processes such as development, differentiation and homeostasis. We employ high-resolution in vitro approaches as well as complementary in vivo approaches that include genomic and proteomic techniques. With these studies we will explore one of the most basic and conserved mechanisms in biology; the translation of genetic information into proteins. Despite decades of research in translation, fundamental questions regarding the fidelity of translation and the processing of damaged mRNAs by the ribosome remain unanswered.
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 multiple quality control processes for clearing aberrant mRNAs exist.
Our primary focus is oxidative damage to RNA due to its prevalence. Initially, we are studying how oxidized base 8-oxoguanine, which can mis-pair with adenine, 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.