Mutagen–oligonucleotide complexes with a bulged base as models for frameshift mutation

Abstract

ACRIDINES and ethidium are frameshift mutagens¹ which intercalate into DNA and RNA², and into minihelices^3,4 made of complementary dinucleotides. However, this intercalation does not provide an explanation of their mutagenic action. Frameshift mutagenesis requires a bulge of one or two bases in either the parent strand (a deletion mutation), or in the newly synthesised strand (an addition mutation). That is, for frameshift mutation to occur, some bases must remain unpaired and outside the normal double helix during replication. We have prepared minihelices containing such bulged bases stabilised by ethidium. Nuclear magnetic resonance (NMR) studies reported here provide strong evidence that a mixture of the oligonucleotides GpUpG plus CpC in the presence of ethidium produces a minihelix containing two G·C base pairs with the uracil base bulged outside the helix and the ethidium intercalated. Similarly, CpUpG forms minihelices in the presence of ethidium containing bulged bases on both strands. These complexes provide models for the mutagenic action of ethidium.