title: Molecular insight into arsenic toxicity via the genome-wide deletion mutant screening of Saccharomyces cerevisiae.
abstract: Arsenic is omnipresent in soil, air, food and water. Chronic exposure to arsenic is a serious problem to human health. In-depth understanding of this metalloid's toxicity is a fundamental step towards development of arsenic-free foods and measures for bioremediation. By screening the complete set of gene deletion mutants (4873) of Saccharomyces cerevisiae, this study uncovered 75 sensitive and 39 resistant mutants against arsenite [As(III)]. Functional analysis of the corresponding genes revealed the molecular details for its uptake, toxicity and detoxification. On the basis of the hypersensitivity of yap3Δ, the transcription factor, Yap3p, is for the first time linked to the cell's detoxification against As(III). Apart from confirming the previously described role of the mitogen-activated protein kinase (MAPK) Hog1 pathway in combating arsenic toxicity, the results show that the regulatory subunits (Ckb1p and Ckb2p) of protein kinase CK2 are also involved in the process, suggesting possible crosstalk between the two key protein kinases. The sensitivity to As(III) conferred by deletion of the genes involved in protein degradation and chromatin remodelling demonstrates protein damage is the key mode of toxicity for the metalloid. Furthermore, the resistant phenotype of fps1Δ, snf3Δ and pho81Δ against As(III) links arsenic uptake with the corresponding plasma membrane-bound transporters-aquaglyceroporin (Fps1p), hexose (Snf3p) and phosphate transporters. The molecular details obtained in this screen for As(III) uptake, detoxification and toxicity provide the basis for future investigations into arsenic-related problems in the environment, agriculture and human health.
authors.affiliation: School of Science and Health, Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, Australia. m.wu@uws.edu.au.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Johnson
authors.affiliation: School of Science and Health, Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, Australia. m.wu@uws.edu.au.
authors.forename: Filip
authors.initials: F
authors.lastname: Veljanoski
authors.affiliation: School of Science and Health, Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, Australia. m.wu@uws.edu.au.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: O'Doherty
authors.affiliation: School of Science and Health, Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, Australia. m.wu@uws.edu.au.
authors.forename: Mohammad S
authors.initials: MS
authors.lastname: Zaman
authors.affiliation: School of Science and Health, Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, Australia. m.wu@uws.edu.au.
authors.forename: Gayani
authors.initials: G
authors.lastname: Petersingham
authors.affiliation: School of Science and Health, Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, Australia. m.wu@uws.edu.au.
authors.forename: Trevor D
authors.initials: TD
authors.lastname: Bailey
authors.affiliation: Department of Pharmacology, School of Medicine and Molecular Medicine Research Group, Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, Australia.
authors.forename: Gerald
authors.initials: G
authors.lastname: Münch
authors.affiliation: School of Science and Health, Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, Australia. m.wu@uws.edu.au.
authors.forename: Cindy
authors.initials: C
authors.lastname: Kersaitis
authors.affiliation: School of Science and Health, Western Sydney University, Locked Bag 1797, Penrith, NSW 2751, Australia. m.wu@uws.edu.au.
authors.forename: Ming J
authors.initials: MJ
authors.lastname: Wu
mesh_terms: D001151:Arsenic / Q000633:toxicity*; D004271:DNA, Fungal / Q000187:drug effects / Q000235:genetics; D004785:Environmental Pollutants / Q000633:toxicity*; D016681:Genome, Fungal / Q000187:drug effects*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics; D017384:Sequence Deletion / Q000187:drug effects* / Q000235:genetics*
chemical_list: D004271:DNA, Fungal; D004785:Environmental Pollutants; D001151:Arsenic