STRUCTURE AND MECHANISM OF DNA INTERSTRAND CROSSLINKING

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Research is proposed in the area of nucleic acid chemistry. Covalent reactions of DNA interstrand crosslinking agents will be investigated. The chemical structures of two interstrand crosslinks, those of a nitrogen mustard and of a highly simplified analog of reductively activated mitomycin C, will be determined at atomic resolution by hydrolysis of structurally homogeneous, interstrand crosslinked DNA fragments containing these crosslinks. The structures of the resulting conjugates will be identified by comparison to authentic, synthetic samples of the expected conjugates. The mechanism by which mitomycin analogs preferentially crosslink 5'-CG sequences in DNA will be investigated using rationally designed synthetic analogs, the interstrand crosslinking sequence preferences of which will be determined at nucleotide resolution. Bifunctional alkylating agents expected on mechanistic grounds to preferentially crosslink the base sequence 5'-GC will be synthesized and studied. DNA interstrand crosslinking agents capable of recognizing and crosslinking a six base pair sequence of DNA will be designed and evaluated.