Professor Chris Grant
Molecular Responses to Oxidative Stress
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. Such 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. To protect against damage, cells contain effective defence mechanisms including enzymes, such as catalase, superoxide dismutase and glutathione peroxidase, and antioxidants including glutathione (GSH) and vitamins C and E. Oxidative damage has been recognised for some time as being associated with various disease processes including cancer, ageing and neurodegenerative disorders. It is also of particular concern to industry, and yeast cells used in the baking and brewing industries are exposed to oxidative stresses during freezing and drying. Thus, understanding the causes of oxidative stress, and in turn, the molecular responses to such stress, is of fundamental importance to many biological questions.
We have characterized the activity and expression of yeast antioxidants and stress response molecules in order to obtain a global overview of the molecular events occurring in cells exposed to oxidative stress conditions. A major focus has been to characterize the role of sulphydryl regulation and we have defined the functional overlap between the thioredoxin and glutaredoxin systems, which are the major redox regulatory systems. This work has shown that independent redox regulation of these systems enables cells to survive under conditions where the glutaredoxin system is oxidized and inactive (1-3). This is important given the established links between defective thiol regulation and disease. More recently, We have demonstrated that the thioredoxin system can prevent protein aggregation and functions to chaperone misassembled ribosomal proteins (4,5). This led to our recent finding that the Tsa1 peroxiredoxin suppresses the de novo formation of the [PSI+] prion in yeast (6). This is an important finding since the molecular basis by which mammalian and fungal prions arise spontaneously is poorly understood.
We have analysed the changes in gene expression following oxidative stress, focussing on post-transcriptional control mechanisms. A range of global techniques, including microarray analysis and proteomics have provided the first evidence that regulating the translational machinery at multiple levels is used to modulate the proteomic output in response to stress conditions (7,8). Our studies have shown that the response to oxidative stress is mediated by oxidant-specific regulation of translation initiation, emphasizing our current view that post-transcriptional controls are crucial mechanisms underlying the ability of all cells to adapt to stress conditions (9).
1. Greetham, D., and Grant, C. M. (2009) Mol. Cell. Biol. 29, 3229-3240
2. Trotter, E. W., and Grant, C. M. (2003) EMBO Reports 4, 184-189
3. Trotter, E. W., and Grant, C. M. (2005) Eukaryot. Cell 4, 392-400
4. Rand, J. D., and Grant, C. M. (2006) Mol. Biol. Cell 17, 387-401.
5. Trotter, E. W., Rand, J. D., Vickerstaff, J., and Grant, C. M. (2008) Biochem J. 412, 73-80
6. Sideri, T. C., Stojanovski, K., Tuite, M. F., and Grant, C. M. (2010) Proc. Natl. Acad. Sci. U .S .A. 107, 6394-6399
7. Shenton, D., Perrone, G., Quinn, K. A., Dawes, I. W., and Grant, C. M. (2002) J. Biol. Chem. 277, 16853-16859.
8. Shenton, D., Smirnova, J. B., Selley, J. N., Carroll, K., Hubbard, S. J., Pavitt, G. D., Ashe, M. P., and Grant, C. M. (2006) J. Biol. Chem. 281, 29011-29021.
9. Mascarenhas, M., et al (2008) Mol. Biol. Cell 19, 2