Lack of Z-DNA Conformation in Mitomycin-Modified Polynucleotides Having Inverted Circular Dichroism

Abstract

Poly(dG-dC)· poly(dG-dC) and Micrococcus lysodeikticus DNA were modified by exposure to reductively activated mitomycin C, an antitumor antibiotic. The resulting covalent drug-polynucleotide complexes displayed varying degrees of CD inversions, which are strikingly similar to the inverted spectrum observed with Z-DNA. The following criteria have been used to establish, however, that the inverted CD pattern seen in mitomycin C-polynucleotide complexes does not reflect a Z-DNA conformation. (i) The ethanol-induced transition of poly(dG-dC)· poly(dG-dC) from B to Z conformation is not facilitated but rather is inhibited by mitomycin C modification. This may be due to the presence of crosslinks. (ii) Radioimmunoassay indicated no competition for Z-DNA-specific antibody by any of the mitomycin C-modified polynucleotides. (iii) 31P NMR of the complexes yielded a single relatively narrow resonance, which is inconsistent with the dinucleotide repeat characteristic of Z-DNA. Alternative explanations for the inverted CD pattern include a drug-induced left-handed but non-Z conformational change or the superposition of an induced CD onto the CD of B-DNA due to drug-base electronic interactions. These results illustrate the need for caution in interpreting CD changes alone as an indication of Z-DNA conformation.

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