This proposal describes genetic and biochemical studies that are aimed at developing a better understanding of the effects of hazardous chemicals on eukaryotic organisms. The investigators want to decipher how eukaryotes sense hazardous chemicals and how they mount defensive responses. A central aim of these studies is to understand the signal transduction mechanisms that control gene expression in response to exposure to toxic chemicals. This type of knowledge will be crucial for understanding the effects of toxic chemicals on human health. A critical long-term goal of these studies will be the development of new strategies to improve detection of environmental toxins. Arsenic and cadmium will be emphasized in these investigations, although hydrogen peroxide will also be used as an efficient and specific method of inflicting oxidative stress. The fission yeast Schizosaccharomyces pombe will be used as the experimental organism for these studies. Fission yeast has be valuable model system for studying basic features of genotoxic and cytotoxic stress response mechanisms that are conserved amongst most eukaryotes, including mammals and plants. In the last funding period the investigators identified Csxl, a novel RNA-binding protein that controls global patterns of gene expression in response to oxidative stress In the upcoming funding period we propose to further these studies and to expand our area of investigation to include a functional genomics screen of genes whose expression is regulated in response to cadmium and arsenic exposure. They also plan to develop yeast strains that have arsenic and cadmium induced genes fused to readily detectable biomarkers. The project has three Specific Aims: 1) to understand how Csxl controls gene expression in response to oxidative stress. Csxl controls mRNA turnover during oxidative stress. All the mRNAs will be defined that are directly regulated by Csxl and investigate Cip1 and Cip2, two Csxl-interacting proteins. that play important roles in controlling gene expression in response to oxidative stress. The other Specific Aims are to 2) carry out a functional genomics screen to identify novel genes that play significant roles in tolerance of cadmium and arsenic, and 3) develop specific biomarkers for arsenic and cadmium.
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