Translational regulation of gene expression during oxidative stress conditions

Our research efforts are aimed at understanding the responses of eukaryotic cells to oxidative stress using the yeast Saccharomyces cerevisiae as a model organism. All aerobic organisms are exposed to reactive oxygen species (ROS) during the course of normal aerobic metabolism or following exposure to radical-generating compounds. ROS can cause wide-ranging damage to cells and an oxidative stress is said to occur when the cellular survival mechanisms are unable to cope with the ROS or the damage caused by them. Oxidative damage is associated with various disease processes including cancer, ageing and neurodegenerative disorders and it is also of particular concern to industry including biotech, brewing and baking. This means that understanding the causes and the molecular responses to oxidative stress is of broad fundamental importance. This specific focus of this project is the role of translation in regulating gene expression in response and adaptation to oxidative stress conditions. The yeast Saccharomyces cerevisiae has a wide variety of industrial applications many of which are impacted upon by its capacity to synthesis proteins under conditions of stress. Thus identifying and characterizing regulatory mechanisms that control protein production during stress conditions will benefit industrial researchers, interested in maximising protein production from biological systems for biotechnological and biopharmaceutical applications.

Although the regulation of the transcription of selected genes has been extensively studied, there is growing appreciation that the selection of the mRNA to be translated is also tightly regulated. Translation initiation is a crucial step for this selection and misregulation of this process has been linked with a plethora of diseases. Cells typically respond to an oxidative stress by inhibiting translation initiation. This reduction in protein synthesis prevents continued gene expression during potentially error-prone conditions as well as allowing for the turnover of existing mRNAs and proteins whilst gene expression is reprogrammed to deal with the stress. Although oxidative stress is widely inhibitory to protein synthesis, translational induction of specific mRNAs is critically important for adaptation to it. This project will use cutting edge technology to examine how oxidative stress regulates translation focussing on identifying and characterizing examples of mRNA-specific regulation which are required for oxidative stress tolerance. Using the yeast model, we have preliminary evidence supporting a regulatory role for the evolutionarily conserved eIF4G translation initiation factor in regulating the translational response to oxidative stress. This project aims to understand the role of eIF4G during oxidative stress which is important since its dysregulation has been implicated in many disease processes and ageing.