Lack of Z-DNA conformation in mitomycin-modified polynucleotides having inverted circular dichroism.

Abstract

Poly(dG-dC).cntdot.poly(dG-dC) and Micrococcus lysodeikticus [M. luteus] DNA were modified by exposure to reductively activated mitomycin C, an antitumor antibiotic. The resulting covalent drug-polynucleotide complexes displayed varying degrees of CD [circular dichroism] inversions, which are strikingly similar to the inverted spectrum observed with Z-DNA. Criteria were used to establish that the inverted CD pattern seen in mitomycin C-polynucleotide complexes does not reflect a Z-DNA conformation. The ethanol-induced transition of poly(dG-dC).cntdot.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. Radioimmunoassay indicated no competition for Z-DNA-specific antibody by any of the mitomycin C-modified polynucleotides. 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 along as an indication of Z-DNA conformation.