A Saccharomyces cerevisiae phleomycin-sensitive mutant, ph140, is defective in the RAD6 DNA repair gene.
The antibiotic bleomycin is used as an anticancer agent for treating a variety of tumours. The antitumour effect of bleomycin is related to its ability to produce lesions such as apurinic/apyrimidinic sites and single- and double-strand breaks in the cellular DNA. Phleomycin is a structurally related form of bleomycin, but it is not used as an anticancer agent. While phleomycin can also damage DNA, neither the exact nature of these DNA lesions nor the cellular process that repairs phleomycin-induced DNA lesions is known. As a first step to understand how eukaryotic cells provide resistance to phleomycin, we used the yeast Saccharomyces cerevisiae as a model system. Several phleomycin-sensitive mutants were generated following gamma-radiation treatment and among these mutants, ph140 was found to be the most sensitive to phleomycin. Molecular analysis revealed that the mutant ph140 harbored a mutation in the DNA repair gene RAD6. Moreover, a functional copy of the RAD6 gene restored full phleomycin resistance to strain ph140. Our findings indicate that the RAD6 protein is essential for yeast cellular resistance to phleomycin.
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C H
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Health and Environement Unit, Centre hospitalier de 1'Université Laval, Sainte-Foy, Canada.
Masson
J Y
JY
Ramotar
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D015112:4-Nitroquinoline-1-oxide / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001761:Bleomycin / Q000494:pharmacology; D004260:DNA Repair / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D004352:Drug Resistance, Microbial / Q000235:genetics; D005800:Genes, Fungal; D008025:Ligases / Q000235:genetics*; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D009154:Mutation; D010692:Phleomycins / Q000494:pharmacology*; D015183:Restriction Mapping; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins; D044763:Ubiquitin-Conjugating Enzymes
D000903:Antibiotics, Antineoplastic; D010692:Phleomycins; D029701:Saccharomyces cerevisiae Proteins; D001761:Bleomycin; D015112:4-Nitroquinoline-1-oxide; D008741:Methyl Methanesulfonate; C471606:RAD6 protein, S cerevisiae; D044763:Ubiquitin-Conjugating Enzymes; D008025:Ligases