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 anti cancer agent. While phleomycin can also damage DNA, neither the exact nature of these DNA lesions nor the cellular process that repairs phle omycin-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-sensiti ve mutants were generated following gamma-radiation treatment and amon g these mutants, ph140 was found to be the most sensitive to phleomyci n. Molecular analysis revealed that the mutant ph140 harbored a mutati on in the DNA repair gene RAD6. Moreover, a functional copy of the RAD 6 gene restored full phleomycin resistance to strain ph140. Our findin gs indicate that the RAD6 protein is essential for yeast cellular resi stance to phleomycin.