Role of base excision repair in protecting cells from the toxicity of chloroethylnitrosoureas.
The chloroethylnitrosoureas react extensively with cellular DNA to produce a variety of DNA adducts, including a deoxycytidine-deoxyguanosine (dC-dG) cross-link that is clearly cytotoxic. It is now well established that O6-alkylguanine-DNA-alkyltransferase can prevent formation of this dC-dG cross-link and thereby diminish the toxicity of the chloroethylnitrosoureas. Besides alkyltransferase, DNA glycosylases from various species can also contribute to cellular resistance to the chloroethylnitrosoureas, but the mechanism for this increased resistance has not been established. It is known, however, that several chloroethylnitrosoureas-modified DNA bases, including the exocyclic adduct, N2,3-ethanoguanine, are released by Escherichia coli 3-methyladenine DNA glycosylase II. In the study described here, we examined the possibility that this enzyme might act on the exocyclic intermediate in dC-dG formation, 1,O6-ethanodeoxyguanosine, and prevent-dC-dG cross-linking in this way. However, the presence of E. coli 3-methyladenine DNA glycosylase II does not decrease the amount of dC-dG cross-link formed when chloroethylnitrosourea reacts with DNA, and we conclude that this enzyme does not recognize 1,O6-ethanodeoxyguanosine. Therefore, its contribution to resistance probably resides in its action on other nitrosourea-induced DNA modifications.
Ludlum
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Department of Pharmacology & Molecular Toxicology, University of Massachusetts Medical School, Worcester 01655-0126, USA.
Li
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Matijasevic
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D002851:Chromatography, High Pressure Liquid; D003432:Cross-Linking Reagents / Q000378:metabolism; D018736:DNA Adducts / Q000032:analysis / Q000378:metabolism*; D045647:DNA Glycosylases; D004260:DNA Repair; D004926:Escherichia coli / Q000201:enzymology; D005038:Ethylnitrosourea / Q000031:analogs & derivatives* / Q000633:toxicity; D008956:Models, Chemical; D009699:N-Glycosyl Hydrolases / Q000378:metabolism; D013379:Substrate Specificity
D003432:Cross-Linking Reagents; D018736:DNA Adducts; C017139:1-(2-chloroethyl)-1-nitrosourea; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; C076131:DNA-3-methyladenine glycosidase II; D005038:Ethylnitrosourea