Sequence Preferences of DNA Interstrand Crosslinkers

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With support from the Organic Dynamics Program, Dr. Hopkins will study the chemical structures of two DNA interstrand crosslinks, i.e., those that result from reaction of DNA (i) with a nitrogen mustard and (ii) with an analog of reductively activated mitomycin C. An investigation of the mechanism by which mitomycin analogs preferentially crosslink 5'-CG sequences in DNA will be performed along with studies of the sequence preferences of several other interstrand DNA crosslinking agents. %%% DNA interstrand covalent crosslinking reactions involve addition of a nucleophilic center on DNA to an electrophilic center of the crosslinking agent. These are fundamentally simple chemical reactions that take place on a structurally and dynamically complex macromolecule. Dr. Hopkins' study is designed to provide information regarding the covalent structures of crosslinked DNAs at the nucleotide level and in some cases will provide information regarding atomic connectivities. Information that Dr. Hopkins obtained from these studies is likely to lead to simplification and improvement in the design of new DNA crosslinking agents.