Investigation of cell responses to reactive oxygen species

Reactive oxygen species (ROS) can arise in cells due to environmental exposure to oxidising agents or from normal processes. High levels of ROS (oxidative stress) can damage DNA, proteins and lipids and consequently are linked with common age-related diseases such as cardiovascular and neurodegenerative diseases andalso decreased lifespan. However, in contrast to these negative impacts, there is increasing evidence that low levels of ROS play beneficial roles in the regulation of essential cellular processes by acting as signalling effector molecules. Thus, in order to understand the relationships between ROS and human health including healthy ageing, and to underpin attempts to develop effective clinical strategies, it is important to discern how cells distinguish and respond appropriately to different types and levels of ROS. Recent work by us and others, using yeast and mammalian cell models, revealed that conserved antioxidants and the relative sensitivity to oxidation of catalytic cysteine residues in enzymes, such as those which influence cell cycle progression, are central to mechanisms underlying sensing and signalling different types and levels of ROS (1-3). For example, we demonstrated that the specific sensitivity of the conserved cell cycle-linked ubiquitin pathway enzyme Cdc34 to cysteine oxidation coordinates cell cycle delay to prevent oxidative stress-induced damage (3). Thus, the project aim is to build on our exciting published and pilot data, using yeast (Saccharomyces cerevisiae) and potentially mammalian cells as model systems, to reveal how the regulation of protein oxidation determines cell responses to different types and levels of ROS. Broadly applicable experience will be obtained of genetics, biochemical, cell biology, microscopy, molecular biology techniques, and also techniques to investigate protein oxidation and responses to ROS.