The long-term objective of this research is to understand the transcriptional mechanisms essential to the cellular response to oxidative stress. Proper transcriptional regulation during oxidative stress is a vital defense mechanism employed by all cells. Oxidative stress occurs when reactive oxygen species overwhelm the battery of cellular antioxidants. The result of this attack causes damage to all organisms and is implicated in the development of many age-related human ailments. Therefore, it is necessary to understand the mechanisms surrounding the primary response to oxidative stress: transcriptional regulation of genes encoding protective proteins. Since transcriptional mechanisms and the response to oxidative stress are highly conserved, the yeast Saccharomyces cerevisiae will serve as a model organism. We have previously identified a novel form of regulation occurring on a gene essential during oxidative stress, the FLR1 gene. Interestingly, at this gene the primary activator Yap1 acts on a pre-assembled RNA polymerase II complex. It is unknown how many other oxidative stress responsive genes display this type of regulation. Toward the goal of understanding the transcriptional mechanisms surrounding the cellular response to oxidative stress, I have proposed two specific aims: 1) Delineate the promoter attributes critical for proper expression of the oxidative stress response gene, FLR1;2) Determine the conservation of Yap1-mediated activation and nuclear spatial positioning between FLR1 and other Yap1 regulated oxidative stress genes. The yeast system facilitates the use of methods from genetics, biochemistry, molecular biology, and cellular biology to unravel these mechanisms. This project is essential to developing a better understanding of the mechanisms surrounding the cellular response to oxidative stress. This is relevant to human health as an inappropriate response to oxidative stress is implicated in many age-related ailments including cancer, neurodegenerative diseases, and cardiovascular disease. Understanding the proper response to oxidative stress is necessary for future development of therapies aimed at preventing the development and exacerbation of these diseases.
| Lee, Sarah K; Fletcher, Aaron G L; Zhang, Lei et al. (2010) Activation of a poised RNAPII-dependent promoter requires both SAGA and mediator. Genetics 184:659-72 |
