title: Synthesis of the prototype DNA-protein cross-link, 1-(guan-1-yl)-2-(cysteine-S-yl)ethane, and its role in the reactions of the haloethylnitrosoureas.
abstract: The haloethylnitrosoureas form a cytotoxic DNA cross-link in a series of reactions which involves initial alkylation of the O6 position of guanine and rearrangement to the intermediate, 1,O6-ethanoguanine; 1,O6-ethanoguanine then reacts with a neighboring cytosine base. O6-Alkylguanine-DNA alkyltransferase can interrupt this process after the initial alkylation step by removing the alkyl group from the O6 position of guanine. Recent evidence suggests that the O6-alkylguanine-DNA alkyltransferase also recognizes 1,O6-ethanoguanine as a substrate, becoming bound to DNA when it interacts with that intermediate. It has also been shown that glutathione becomes bound to haloethylnitrosourea-treated DNA, apparently through chemical interaction with 1,O6-ethanoguanine. Since both of these reactions involve the thiol group of cysteine, we have examined the reaction of cysteine with 1,O6-ethanoguanine, characterizing the prototype DNA-protein cross-link, 1-(3-cytosinyl),2-(1-guanyl)ethane, which is formed in this reaction. These results establish a competitive reaction with 1,O6-ethanoguanine as a likely route to protein-DNA cross-linking.
authors.affiliation: Department of Pharmacology, University of Massachusetts Medical School, Worcester 01655.
authors.forename: T
authors.initials: T
authors.lastname: Niu
authors.forename: D
authors.initials: D
authors.lastname: Yu
authors.forename: M C
authors.initials: MC
authors.lastname: Kirk
authors.forename: D B
authors.initials: DB
authors.lastname: Ludlum
mesh_terms: D003432:Cross-Linking Reagents / Q000138:chemical synthesis / Q000494:pharmacology; D003545:Cysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004249:DNA Damage; D004347:Drug Interactions; D005038:Ethylnitrosourea / Q000031:analogs & derivatives / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D013056:Spectrophotometry, Ultraviolet
chemical_list: D003432:Cross-Linking Reagents; C079838:1-(guan-1-yl)-2-(cystein-S-yl)ethane; D006147:Guanine; D004247:DNA; D003545:Cysteine; D005038:Ethylnitrosourea