Functional mitochondria are essential for Saccharomyces cerevisiae cellular resistance to bleomycin.
The antitumor activity of bleomycin is associated with its ability to produce DNA lesions. The cellular process that repairs bleomycin-induced DNA lesions is not entirely clear. To understand how these DNA lesions are repaired in eukaryotic cells, we used mini Tn3 : : LEU2 :: LacZ transposon mutagenesis to isolate yeast mutants that were hypersensitive to bleomycin. One of the mutants, HCY69, was characterized further and found to be 4- and 3-fold more sensitive, respectively, to bleomycin and hydrogen peroxide, as compared to the parent. The mutant displayed parental resistance to a variety of other DNA-damaging agents. Plasmid rescue and DNA sequence analysis revealed that the transposon interrupted the OXA1 gene, which encodes a protein required to process one of the subunits, cox II, of the cytochrome oxidase complex in mitochondria. A plasmid carrying the native OXA1 gene fully restored drug resistance to strain HCY69. Our data strongly suggest that functional mitochondria are required for cellular protection against the toxic effects of bleomycin.
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CHUL Research Center, Health and Environment Unit, 2705 Laurier Blvd, Sainte-Foy, Québec, G1V 4G2, Canada.
Masson
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Ramotar
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D001761:Bleomycin / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects; D004251:DNA Transposable Elements; D004352:Drug Resistance, Microbial / Q000235:genetics*; D003576:Electron Transport Complex IV; D017353:Gene Deletion; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics*; D024101:Mitochondrial Proteins; D016296:Mutagenesis; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D016877:Oxidants / Q000494:pharmacology; D010641:Phenotype; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics*
D004251:DNA Transposable Elements; D024101:Mitochondrial Proteins; D009687:Nuclear Proteins; C090858:OXA1 protein; D016877:Oxidants; D001761:Bleomycin; D003576:Electron Transport Complex IV