Comparative Functional Genomic Analysis Identifies Distinct and Overlapping Sets of Genes Required for Resistance to Monomethylarsonous Acid (MMAIII) and Arsenite (AsIII) in Yeast

• Published in: Toxicological sciences Vol. 111; no. 2; pp. 424 - 436
• Main Authors: Jo, William J., Loguinov, Alex, Wintz, Henri, Chang, Michelle, Smith, Allan H., Kalman, Dave, Zhang, Luoping, Smith, Martyn T., Vulpe, Chris D.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01-10-2009
• Subjects: arsenic; arsenite; Arsenites - toxicity; Chromatin - genetics; DNA Repair; Drug Resistance, Microbial; Genome, Fungal; glutathione; Glutathione - metabolism; monomethylarsonous acid; Organometallic Compounds - toxicity; Protein Folding; Saccharomyces cerevisiae - drug effects; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - metabolism; Systems Toxicology; Tubulin - metabolism; yeast; arsenic; glutathione; yeast; arsenite; monomethylarsonous acid
• ISSN: 1096-6080; 1096-0929
• DOI: 10.1093/toxsci/kfp162

Arsenic is a human toxin and carcinogen commonly found as a contaminant in drinking water. Arsenite (AsIII) is the most toxic inorganic form, but recent evidence indicates that the metabolite monomethylarsonous acid (MMAIII) is even more toxic. We have used a chemical genomics approach to identify the genes that modulate the cellular toxicity of MMAIII and AsIII in the yeast Saccharomyces cerevisiae. Functional profiling using homozygous deletion mutants provided evidence of the requirement of highly conserved biological processes in the response against both arsenicals including tubulin folding, DNA double-strand break repair, and chromatin modification. At the equitoxic doses of 150μM MMAIII and 300μM AsIII, genes related to glutathione metabolism were essential only for resistance to the former, suggesting a higher potency of MMAIII to disrupt glutathione metabolism than AsIII. Treatments with MMAIII induced a significant increase in glutathione levels in the wild-type strain, which correlated to the requirement of genes from the sulfur and methionine metabolic pathways and was consistent with the induction of oxidative stress. Based on the relative sensitivity of deletion strains deficient in GSH metabolism and tubulin folding processes, oxidative stress appeared to be the primary mechanism of MMAIII toxicity whereas secondary to tubulin disruption in the case of AsIII. Many of the identified yeast genes have orthologs in humans that could potentially modulate arsenic toxicity in a similar manner as their yeast counterparts.