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 organisms with double-stranded DNA as a direct consequence of oxidative deamination of adenine and of cytosine residues. Here we summarize evidence indicating that other mechanisms are involved in the case of NA-induced G/C-->A/T transition mutations. We present several models for pathways of NA mutagenesis that may account for our experimental results and overlapping data noted in the literature. One model proposes that the base substitution mutations observed are due to DNA alkylation damage mediated via nitrosation of polyamines and/or other ubiquitous cellular molecules. Other models assume that predisposing lesions, such as G-to-G cross-links, are first formed. The cross-links are pictured as leading to perturbations in DNA structure that allow subsequent opportunity for NA-induced deaminations of cytosine residues in their immediate vicinity. The deaminations preferentially result in G/C-->A/T transition mutations at sites highly dependent on adjoining base sequence context (i.e., in NA "mutational hotspots"). A final model proposes that NA-induced G/C-->A/T transition mutations arise mainly from oxidative deamination of guanosine residues and not from deamination of cytosine residues in duplex DNA.