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Direct Demonstration in Synthetic Oligonucleotides that N,N'-Bis(2-chloroethyl)-nitrosourea Cross-Links N¹ of Deoxyguanosine to N³ of Deoxycytidine on Opposite Strands of Duplex DNA¹

Department of Chemistry, University of Washington, Seattle, Washington 98195

The sequence specificity and covalent structure of the lesion caused by the DNA interstrand cross-linking reaction of N,N'-bis(2-chloroethyl)-nitrosourea (BCNU) were investigated using synthetic oligonucleotides. The efficiency of interstrand cross-linking was found to parallel the efficiency of monoadduct formation, preferring deoxyguanosine-deoxycytidine-rich duplexes and, particularly, runs of deoxyguanosine. No explicit sequence specificity was observed. Enzymatic digestion of purified, interstrand cross-linked DNA returned primarily the unmodified deoxynucleosides, along with 1-[N³-deoxycytidyl]-2-[N¹-deoxyguanosyl]ethane. This substance was characterized by comparison of its mass spectrum, high-pressure liquid chromatography retention time, and UV spectrum to an authentic standard prepared by chemical synthesis. These studies provide the first direct evidence that BCNU has no strong sequence preference for interstrand cross-linking and that substance 4, which has been previously isolated from BCNU-treated DNA, derives from alkylation on opposite strands of DNA. The lack of sequence preference and lesion structure together suggest that one source of BCNU interstrand cross-links is linkage of deoxyguanosine and deoxycytidine partners from a single bp.

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