Exploration of the novel genes that affect IRES-mediated translation of URE2, a key gene involved in metal detoxification

Various parts of the world are polluted with different levels of heavy metals and metalloids toxicity. Understanding the molecular mechanisms that drive the detoxification pathways in living organisms plays a crucial role in decontamination efforts. Expression of the detoxifying genes is mediated at both transcriptional and translational levels in the presence of toxic metals. In these conditions, 5’ cap-dependent translation is often down-regulated or even completely inhibited. However, translation of certain mRNAs such as Ureidosuccinate Transport 2 (URE2) is essential for the cell survival in toxic conditions. In the baker yeast Saccharomyces cerevisiae, resistance to a wide range of toxic metals is synchronized by glutathione S-transferase products. Yeast URE2 protein has glutathione peroxidase activity and is homologous to mammalian glutathione S-transferases. In addition to 5’ cap-dependent translation, yeast URE2 mRNA is also translated through an internal structure, free of 5’ cap and eIF4E. URE2 mRNA possesses a unique IRES element between nucleotides 205 and 309 in its coding region. URE2 gene deletion strain is hypersensitive to toxic metals such as Arsenic, Nickel and Cadmium. Here we report on the finding of five genes whose deletion strains exhibit the same phenotype as URE2 mutant. None of these genes were previously linked to metal toxicity. Our gene expression analysis illustrates that these five genes all affect URE2 mRNA expression at the translation level. Our subsequent investigation suggests that the deletion of the five identified genes negatively regulate the translation of URE2 mRNA through its IRES element. Our interaction analysis also showed strong communication between the five identified genes and the genes involved in translational control suggesting novel roles in translation for the five genes.