Abstract
Arsenic (As) and cadmium (Cd) are two of the most hazardous substances in the environment and have been implicated in a number of human diseases including cancer. Their mechanisms of toxicity and subsequent carcinogenesis are not understood. To identify the genes involved in As/Cd detoxification, we screened a random insertional mutagenesis library of Schizosaccharomyces pombe for mutants that are hypersensitive to As/Cd. Mutations were mapped to spc1(+) (sty1(+)) and SPBC17G9.08c. Spc1 is a stress-activated protein kinase orthologous to human p38. A fragment of SPBC17G9.08c was previously identified as csx2, a high-copy suppressor of cut6 that encodes an acetyl-CoA carboxylase involved in fatty acid biosynthesis. SPBC17G9.08c is a member of the centaurin ADP ribosylation factor GTPase activating protein family found in a variety of fungi, plants and metazoans, but not in Saccharomyces cerevisiae. Cnt5, so named because its closest human homolog is centaurin beta-5, binds to phosphatidic acid and phosphatidyl serine in vitro. Microscopic localization of Cnt5-GFP indicates significant redistribution of Cnt5 from the cytoplasm to the cell membranes in response to As stress. These data suggest a model in which Cnt5 contributes to As/Cd resistance by maintaining membrane integrity or by modulating membrane trafficking.