title: Centaurin-like protein Cnt5 contributes to arsenic and cadmium resistance in fission yeast.
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.
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Ajay Amar
authors.initials: AA
authors.lastname: Vashisht
authors.forename: Patrick Joseph
authors.initials: PJ
authors.lastname: Kennedy
authors.forename: Paul
authors.initials: P
authors.lastname: Russell
mesh_terms: D000595:Amino Acid Sequence; D001151:Arsenic / Q000633:toxicity*; D002104:Cadmium / Q000633:toxicity*; D002462:Cell Membrane / Q000737:chemistry; D003593:Cytoplasm / Q000737:chemistry; D004251:DNA Transposable Elements; D025141:Drug Resistance, Fungal; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D010712:Phosphatidic Acids / Q000378:metabolism; D010718:Phosphatidylserines / Q000378:metabolism; D012568:Schizosaccharomyces / Q000187:drug effects* / Q000235:genetics; D016415:Sequence Alignment
chemical_list: D004251:DNA Transposable Elements; D005656:Fungal Proteins; D010712:Phosphatidic Acids; D010718:Phosphatidylserines; D002104:Cadmium; D049452:Green Fluorescent Proteins; D001151:Arsenic