PROTECTION AGAINST CHLOROETHYLNITROSOUREA CYTOTOXICITY BY EUKARYOTIC 3-METHYLADENINE DNA GLYCOSYLASE

A eukaryotic 3-methyladenine DNA glycosylase gene, the Saccharomyces c erevisiae MAG gene, was shown to prevent N-(2-chloroethyl)-N-nitrosour ea toxicity. Disruption of the MAG gene by insertion of the URA3 gene increased the sensitivity of S. cerevisiae cells to N-(2-chloroethyl)- N-nitrosourea, and the expression of MAG in glycosylase-deficient Esch erichia coli cells protected against the cytotoxic effects of N-(2-chl oroethyl)-N-nitrosourea. Extracts of E. coli cells that contain and ex press the MAG gene released 7-hydroxyethyl-guanine and 7-chloroethylgu anine from N-(2-chloroethyl)-N-nitrosourea-modified DNA in a protein- and time-dependent manner. The ability of a eukaryotic glycosylase to protect cells from the cytotoxic effects of a haloethylnitrosourea and to release N-(2-chloroethyl)-N-nitrosourea-induced DNA modifications suggests that mammalian glycosylases may play a role in the resistance of tumor cells to the antitumor effects of the haloethylnitrosoureas.