MOLECULAR-MODELS THAT MAY ACCOUNT FOR NITROUS-ACID MUTAGENESIS IN ORGANISMS CONTAINING DOUBLE-STRANDED DNA

Nitrous acid (NA) is often presumed to cause base substitutions in org anisms with double-stranded DNA as a direct consequence of oxidative d eamination of adenine and of cytosine residues. Here we summarize evid ence indicating that other mechanisms are involved in the ca se of NA- induced G/C --> A/T transition mutations. We present several models fo r pathways of NA mutagenesis that may account for our experimental res ults and overlapping data noted in the literature. One model proposes that the base substitution mutations observed are due to DNA alkylatio n damage mediated via nitrosation of polyamines and/or other ubiquitou s cellular molecules. Other models assume that pre-disposing lesions, such as G-to-G cross-links, ore first formed. The cross-links are pict ured as leading to perturbations in DNA structure that allow subsequen t opportunity for NA-induced deaminations of cytosine residues in thei r immediate vicinity. The deaminations preferentially result in G/C--> A/T transition mutations at sites highly dependent on adjoining base s equence context (i.e., in NA ''mutational hotspots''). A final model p roposes that NA-induced G/C-->A/T transition mutations arise mainly fr om oxidative deamination of guanosine residues and not from deaminatio n of cytosine residues in duplex DNA. (C) 1994 Wiley-Liss, Inc.