Sequence-selective binding of an ellipticine derivative to DNA

Abstract

The DNA sequence specificity of an ellipticine derivative bearing an aminoalkyl side chain has been determined by a variety of footprinting methods. The drug exhibits sequence selective binding and discriminates against runs of adenines or thymines. Binding is shown to occur at various sequences with a preference for GC rich regions of DNA. A large enhancement of DNAase I and of hydroxyl radical cleavage in regions rich in A's or T's is observed together with hyperreactivity of adenines towards diethylpyrocarbonate in the presence of drug. This indicates the occurrence of drug-induced changes in critical conformational features of DNA. The total absence of hyperreactivity of guanine residues towards diethylpyrocarbonate appears to be related to the sequence selectivity of drug binding. No alteration of the dimethyl sulphate and methylene blue-induced cleavage of DNA is observed. Irradiation of ellipticine derivative-DNA complexes with UV light followed by alkali treatment leads to selective photocleavage at guanine residues, consistent with the deduced degree of selectivity of the binding reaction.