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, since they are known to damage DNA and exposure is linked to cancer incidence. 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 predominantly C/G → A/T, C/G → T/A, and T/A → C/G substitutions, each in similar proportions. We 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 mutational signature of unknown etiology. We also noted that acetaldehyde treatment caused an excess of deletion events longer than four bases while formaldehyde did not. This latter result could be another distinguishing feature between the mutational patterns of these simple aldehydes. These findings shed new light on the characteristics of two important, commonly occurring mutagens.

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

“…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][51][52][53][54][55].…”

“…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].…”

Aldehyde-Associated Mutagenesis─Current State of Knowledge

“…(Figure ). In fact, most cancers are marked by replication stress, replication–transcription collisions and R-loop formation, and hypertranscription, all events that generate copious ssDNA. , As such, mutations in ssDNA regions could represent a genomic record of aldehyde exposures, such as what we and others have demonstrated. , …”

“…Interestingly, the enriched mutations observed in cancers strongly associated with the nontranscribed strand of genes, which suggests that ssDNA formed during increased transcription in cancers likely acts as an ideal substrate for acetaldehyde-induced mutagenesis . A related study demonstrated the mutagenesis of ssDNA in response to acetaldehyde, albeit with different base substitutions, i.e., more C → T and T → A changes; interestingly, acetaldehyde treatment led to an increase in the proportion of ssDNA-associated deletions of ≥5 bp but without any associated microhomology at break points …”

“…170 A related study demonstrated the mutagenesis of ssDNA in response to acetaldehyde, albeit with different base substitutions, i.e., more C → T and T → A changes; interestingly, acetaldehyde treatment led to an increase in the proportion of ssDNA-associated deletions of ≥5 bp but without any associated microhomology at break points. 171 Formaldehyde Mutagenesis. In budding yeast, formaldehyde-mutated CAN1 mutants and lys2 frameshift revertants were sequenced and found to contain frameshifts consisting of NER-dependent large deletions as well as complex insertions in hotspots of the LYS2 gene.…”