Abstract Saccharomyces cerevisiae was used to uncover the mechanisms underlying tolerance and toxicity of the agricultural fungicide
mancozeb, linked to
cancer and
Parkinson's disease development. Chemogenomics screening of a yeast deletion mutant collection revealed 286 genes that provide protection against
mancozeb toxicity. The most significant Gene Ontology (GO) terms enriched in this dataset are associated to transcriptional machinery, vacuolar organization and biogenesis, intracellular trafficking, and cellular pH regulation. Clustering based on physical and genetic interactions further highlighted the role of oxidative stress response, protein degradation and
carbohydrate/energy metabolism in
mancozeb stress tolerance.
Mancozeb was found to act in yeast as a
thiol-reactive compound, but not as a
free radical or reative
oxygen species (ROS) inducer, leading to massive oxidation of
protein cysteins, consistent with the requirement of genes involved in
glutathione biosynthesis and reduction and in protein degradation to provide
mancozeb resistance. The identification of Botrytis cinerea homologues of yeast
mancozeb tolerance determinants is expected to guide studies on
mancozeb mechanisms of action and tolerance in phytopathogenic fungi. The generated networks of
protein-
protein associations of yeast
mancozeb tolerance determinants and their human orthologues share a high degree of similarity. This toxicogenomics analysis may, thus, increase the understanding of
mancozeb toxicity and adaptation mechanisms in humans.