A ubiquitin-proteasome system is responsible for the protection of yeast and human cells against methylmercury.
The mechanism responsible for the toxic effects of methylmercury (MeHg), an important environmental pollutant, is poorly understood. We have identified a gene, CDC34, that confers resistance to MeHg in Saccharomyces cerevisiae by screening a yeast genomic DNA library. CDC34 encodes a ubiquitin-conjugating enzyme, Cdc34, which is involved in ubiquitin-dependent proteolysis. Overexpression of Cdc34 results in significant resistance to MeHg both in yeast and human cells, and it increases the cellular level of ubiquitinated proteins. The ubiquitin-conjugating activity of Cdc34 is essential for the Cdc34-mediated resistance to MeHg, and the protective effect of the overexpression of Cdc34 is depressed by inhibition of proteasome activity. Our results support the hypothesis that MeHg induces the cellular accumulation of a certain protein(s) that causes cell damage and that this protein(s) is degraded after its ubiquitination in proteasomes.
Hwang
Gi-Wook
GW
Laboratory of Molecular and Biochemical Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan.
Furuchi
Takemitsu
T
Naganuma
Akira
A
D064173:Anaphase-Promoting Complex-Cyclosome; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000502:physiology*; D019610:Cytoprotection; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008025:Ligases / Q000235:genetics / Q000378:metabolism; D008767:Methylmercury Compounds / Q000633:toxicity*; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D014170:Transformation, Genetic; D025801:Ubiquitin / Q000502:physiology*; D044763:Ubiquitin-Conjugating Enzymes; D043743:Ubiquitin-Protein Ligase Complexes
D008767:Methylmercury Compounds; D009097:Multienzyme Complexes; D029701:Saccharomyces cerevisiae Proteins; D025801:Ubiquitin; C577449:CDC34 protein, S cerevisiae; C577447:CDC34 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D008025:Ligases; C004925:methylmercuric chloride