title: Global Fitness Profiling Identifies Arsenic and Cadmium Tolerance Mechanisms in Fission Yeast.
abstract: Heavy metals and metalloids such as cadmium [Cd(II)] and arsenic [As(III)] are widespread environmental toxicants responsible for multiple adverse health effects in humans. However, the molecular mechanisms underlying metal-induced cytotoxicity and carcinogenesis, as well as the detoxification and tolerance pathways, are incompletely understood. Here, we use global fitness profiling by barcode sequencing to quantitatively survey the Schizosaccharomyces pombe haploid deletome for genes that confer tolerance of cadmium or arsenic. We identified 106 genes required for cadmium resistance and 110 genes required for arsenic resistance, with a highly significant overlap of 36 genes. A subset of these 36 genes account for almost all proteins required for incorporating sulfur into the cysteine-rich glutathione and phytochelatin peptides that chelate cadmium and arsenic. A requirement for Mms19 is explained by its role in directing iron-sulfur cluster assembly into sulfite reductase as opposed to promoting DNA repair, as DNA damage response genes were not enriched among those required for cadmium or arsenic tolerance. Ubiquinone, siroheme, and pyridoxal 5'-phosphate biosynthesis were also identified as critical for Cd/As tolerance. Arsenic-specific pathways included prefoldin-mediated assembly of unfolded proteins and protein targeting to the peroxisome, whereas cadmium-specific pathways included plasma membrane and vacuolar transporters, as well as Spt-Ada-Gcn5-acetyltransferase (SAGA) transcriptional coactivator that controls expression of key genes required for cadmium tolerance. Notable differences are apparent with corresponding screens in the budding yeast Saccharomyces cerevisiae, underscoring the utility of analyzing toxic metal defense mechanisms in both organisms.
authors: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037.
authors: Lan
authors: L
authors: Guo
authors: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037.
authors: Abantika
authors: A
authors: Ganguly
authors: National Institute of Biological Sciences, Beijing 102206, People's Republic of China.
authors: Lingling
authors: L
authors: Sun
authors: National Institute of Biological Sciences, Beijing 102206, People's Republic of China.
authors: Fang
authors: F
authors: Suo
authors: National Institute of Biological Sciences, Beijing 102206, People's Republic of China.
authors: Li-Lin
authors: LL
authors: Du
authors: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California 92037 prussell@scripps.edu.
authors: Paul
authors: P
authors: Russell
mesh_terms: D000220:Adaptation, Biological; D001151:Arsenic / Q000378:metabolism / Q000494:pharmacology*; D001692:Biological Transport; D002104:Cadmium / Q000378:metabolism / Q000494:pharmacology*; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D003545:Cysteine / Q000096:biosynthesis; D004249:DNA Damage; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D063990:Gene Ontology; D056084:Genetic Fitness; D000075322:Heavy Metal Poisoning; D026901:Membrane Transport Proteins / Q000378:metabolism; D053858:Metabolic Networks and Pathways; D008826:Microbial Sensitivity Tests; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D020675:Peroxisomes / Q000378:metabolism; D010641:Phenotype; D054811:Phytochelatins / Q000096:biosynthesis; D011041:Poisoning; D012568:Schizosaccharomyces / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D029702:Schizosaccharomyces pombe Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D025101:Vitamin B 6 / Q000378:metabolism
chemical_list: D026901:Membrane Transport Proteins; C560515:Mms19 protein, S pombe; D029702:Schizosaccharomyces pombe Proteins; D014157:Transcription Factors; D002104:Cadmium; D025101:Vitamin B 6; D054811:Phytochelatins; D003545:Cysteine; D001151:Arsenic
keywords: Schizosaccharomyces pombe; arsenic; cadmium; heavy metals; metal toxicity