Protection against chloroethylnitrosourea cytotoxicity by eukaryotic 3-methyladenine DNA glycosylase.
A eukaryotic 3-methyladenine DNA glycosylase gene, the Saccharomyces cerevisiae MAG gene, was shown to prevent N-(2-chloroethyl)-N-nitrosourea 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 Escherichia coli cells protected against the cytotoxic effects of N-(2-chloroethyl)-N-nitrosourea. Extracts of E. coli cells that contain and express the MAG gene released 7-hydroxyethylguanine and 7-chloroethylguanine 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.
Matijasevic
Z
Z
Department of Pharmacology, University of Massachusetts Medical School, Worcester 01655.
Boosalis
M
M
Mackay
W
W
Samson
L
L
Ludlum
D B
DB
D000818:Animals; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism*; D045647:DNA Glycosylases; D004260:DNA Repair; D004351:Drug Resistance; D005038:Ethylnitrosourea / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D005800:Genes, Fungal; D007700:Kinetics; D008322:Mammals; D009699:N-Glycosyl Hydrolases / Q000235:genetics / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology
C017139:1-(2-chloroethyl)-1-nitrosourea; D004247:DNA; C021565:3-methyladenine-DNA glycosylase; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; D005038:Ethylnitrosourea