ToxSci Advance Access originally published online on August 6, 2008
Toxicological Sciences 2008 106(1):124-139; doi:10.1093/toxsci/kfn153
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A Genome-Wide Screen of Genes Involved in Cadmium Tolerance in Schizosaccharomyces pombe
* Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037
Functional Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Yuseong, Daejeon, Republic of Korea
BiONEER Corporation, Daejeon 306-220, Republic of Korea
Cell Cycle Laboratory, Cancer Research UK, London Research Institute, London WC2A 3PX, UK
¶ Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037
2 To whom correspondence should be addressed at Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037. Fax: (858) 784-2265. E-mail: prussell{at}scripps.edu.
Received May 7, 2008; accepted July 21, 2008
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Abstract |
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Cadmium is a worldwide environmental toxicant responsible for a range of human diseases including cancer. Cellular injury from cadmium is minimized by stress-responsive detoxification mechanisms. We explored the genetic requirements for cadmium tolerance by individually screening mutants from the fission yeast (Schizosaccharomyces pombe) haploid deletion collection for inhibited growth on agar growth media containing cadmium. Cadmium-sensitive mutants were further tested for sensitivity to oxidative stress (hydrogen peroxide) and osmotic stress (potassium chloride). Of 2649 mutants screened, 237 were sensitive to cadmium, of which 168 were cadmium specific. Most were previously unknown to be involved in cadmium tolerance. The 237 genes represent a number of pathways including sulfate assimilation, phytochelatin synthesis and transport, ubiquinone (Coenzyme Q10) biosynthesis, stress signaling, cell wall biosynthesis and cell morphology, gene expression and chromatin remodeling, vacuole function, and intracellular transport of macromolecules. The ubiquinone biosynthesis mutants are acutely sensitive to cadmium but only mildly sensitive to hydrogen peroxide, indicating that Coenzyme Q10 plays a larger role in cadmium tolerance than just as an antioxidant. These and several other mutants turn yellow when exposed to cadmium, suggesting cadmium sulfide accumulation. This phenotype can potentially be used as a biomarker for cadmium. There is remarkably little overlap with a comparable screen of the Saccharomyces cerevisiae haploid deletion collection, indicating that the two distantly related yeasts utilize significantly different strategies for coping with cadmium stress. These strategies and their relation to cadmium detoxification in humans are discussed.
Key Words: cadmium; Schizosaccharomyces pombe; gene deletion; sulfur; stress; ubiquinone.
1 These authors contributed equally to this work.
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