Analyses of Mutational Patterns Induced by Formaldehyde and Acetaldehyde Reveal Similarity to a Common Mutational Signature

Abstract

Formaldehyde (CH2O) and acetaldehyde (C2H4O) are reactive small molecules produced endogenously in cells as well as being environmental contaminants. Both of these small aldehydes are classified as human carcinogens, as they are known to damage DNA and cause mutations. However, the mutagenic properties of formaldehyde and acetaldehyde remain incompletely understood, at least in part because they are relatively weak mutagens. Here, we use a highly sensitive yeast genetic reporter system featuring controlled generation of long single-stranded DNA regions to show that both small aldehydes induced mutational patterns characterized by mostly C/G → A/T, C/G → T/A, and T/A → C/G substitutions, each in similar proportions. We also observed an excess of C/G → A/T transversions when compared to mock-treated controls. Many of these C/G → A/T transversions occurred at TC/GA motifs. Interestingly, the formaldehyde mutational pattern resembles single base substitution (SBS) signature 40 from the Catalog of Somatic Mutations in Cancer (COSMIC). SBS40 is a cancer mutational signature of unknown etiology. We also noted that acetaldehyde treatment caused an excess number of deletion events longer than four bases while formaldehyde did not. This latter result could be a distinguishing feature between the mutational patterns of these two simple aldehydes. These findings shed new light on the mutagenic characteristics of two important carcinogens.

Mutagenesis Induced by Protonation of Single-Stranded DNA is Linked to Glycolytic Sugar Metabolism

“…This mutagenesis system is exceptionally well suited to investigating weak mutagens or subtle mutagenic effects, since the ssDNA is more prone to mutation than double-stranded DNA (dsDNA) and high-fidelity repair using the complementary strand would not be possible. The cdc13-1 ssDNA triple reporter gene system has been used previously to elucidate the mutagenic properties of: sodium bisulfite and the human APOBEC3G cytidine deaminase [35]; abasic sites [50]; reactive oxygen species [51]; human APOBEC3A and APOBEC3B cytidine deaminases [52]; alkylating agents [53]; acetaldehyde [54,55]; and formaldehyde [55].…”

“…Depending on the mutagen, the ssDNA reporter can be two to three orders of magnitude more sensitive than dsDNA controls [35]. Indeed, this system has been deployed successfully to elucidate the characteristics of multiple mutagens already [35,50–55].…”