Table 1. Studies Exploring Aldehyde-Associated Mutagenesisa.
| agent | system | chemical agent | reporter | mutagenicity | sequencing | signature | proposed mechanism | ref |
|---|---|---|---|---|---|---|---|---|
| acetaldehyde (AA) | SV-40 transformed fibroblasts | direct AA treatment of reporter plasmid | supF tRNA gene | yes | Sanger | GG → TT (CC → AA) | ICL formation impaired NER | (159) |
| peripheral T lymphocytes | AA | HPRT | yes | Sanger | G → A | transcription-associated NER | (161) | |
| HEK 293 cells | N2-,O6-dG adduct-containing oligos | supF tRNA gene | yes | Sanger | G:C → A:T | error-prone TLS, postreplicative MMR | (163) | |
| human XPA cells | site-specific plasmid-borne adduct | bsd resistance (survival) | yes | Sanger | G → T | ICL formation, TLS | (164) | |
| human fibroblasts | AA | TP53 | yes | Sanger | G → A, G → T | ICL formation, TLS | (165) | |
| mice | AA | HSCs | yes | WGS | aldh2–/–fancd2–/– cells had more base substitutions, microhomology (MH)-mediated deletions, rearrangements, likely stochastic damage | (168) | ||
| human iPSC | AA | no | WGS | DNA damage response induction without mutagenesis | (169) | |||
| Saccharomyces cerevisiae | AA, EtOH | CAN1 | none for AA | Sanger | increased C → T with EtOH | EtOH-induced replication stress, followed by error-prone DNA repair but no AA-specific mutations | (197) | |
| Xenopus egg extracts | AA-ICL adduct plasmid replication | yes | high-throughput sequencing | G → T | Rev1, pol ζ-mediated TLS, ICL repair via FA pathway | (94) | ||
| S. cerevisiae | AA | CAN1 ADE2 | yes | WGS | gCn → gAn (nGc → nTc), ssDNA-specific | TLS mediated by pol ζ, ssDNA-specific signature also observed in alcohol-associated cancers | (170) | |
| S. cerevisiae | AA | CAN1 | yes | WGS | C:G → T:A, T:A → C:G, small deletions | likely TLS | (171) | |
| formaldehyde (FA) | S. cerevisiae | FA | CAN1, lys2ΔA746, NR | yes | Sanger | large deletions in direct repeats, complex insertions | lesion bypass by NER, Pol ζ-mediated TLS | (172) |
| mice | methanol | endogenous N2-hydroxymethyl-dG | DNA damage | increased yH2AX, p53 induction | FA cross-link repair pathway and ADH5 mediated protection | (99) | ||
| human iPSC | FA | no | WGS | no effect on DDR pathway or mutagenesis | (169) | |||
| mice | FA | yes | WGS (HPSCs) | C → T, T → A | SBS signatures 3, 5, 25, 40 observed. age-associated damage, FA pathway defect | (32) | ||
| FA SCCs | likely elevated aldehyde levels from smoking, alcohol | yes | PacBio, WGS | multiple COSMIC SBS and ID signatures | CIN is high in FA cells, likely drives mutagenesis, complex SV formation | (186) | ||
| S. cerevisiae | FA | CAN1 | yes | WGS | C:G → T:A, T:A → C:G, no indels | likely TLS | (171) | |
| acrolein (Acr) | S. typhimurium | Acr | S9 fraction enzyme activation | yes | (175) | |||
| COS-7 cells | pMS2 shuttle vector with adduct (γ-HO-PdG) | yes | Sanger | G → T, G → A, G → C | lesion bypass by error-prone polymerases, DNA:DNA, DNA: protein cross-links | (176) | ||
| NHLF cells | Acr | supF, p53 | yes | Sanger | G → T, G → A, G → C | Acr in cigarette smoke can mutate cancer drivers, NER-mediated bulky lesion repair | (153) | |
| mouse embryonic fibroblasts, human XPA fibroblasts | Acr | cII transgene, supF | no | dose-dependent, chromosome context-dependent mutagenicity of Acr, error-free lesion bypass | (198) | |||
| human CCL-202 lung fibroblasts | Acr | supF | yes | Sanger | G → T, G → A, G → C | Acr mutations scale proportionately with Acr-DNA adducts, NER-dependent repair. | (177) | |
| human iPSC | Acr | no | WGS | no effect on DDR pathway or mutagenesis | (169) | |||
| oxoaldehydes | E. coli | methylglyoxal | lacI | yes | Sanger | G:C → C:G, G:C → T:A | NER-dependent repair | (181) |
| COS-7 | methylglyoxal | supF | yes | Sanger | G:C → C:G, G:C → T:A | NER-dependent repair | (114) | |
| human fibroblasts (XP+ and XP−) | CEdG-adducted shuttle vector | supF | yes | Sanger | A:T → G:C | NER-dependent adduct removal and DNA repair | (182) | |
| COS-7 | glyoxal | supF | yes | Sanger | G:C → C:G, G:C → T:A | NER-dependent repair | (120) | |
| crotonaldehyde | COS-7 cells | N2-,O6-dG adduct-containing vector | GFP vector (transfection efficiency) | yes | probe hybridization | G → T | replication blockage, NER | (132) |
| human XPA-cells | shuttle vector with site-specific ICL | blasticidin S | yes | probe hybridization | G → T | NER-independent repair at replication forks, TLS | (199) | |
| malondialdehyde (MDA) | E. coli | ssDNA M13 vector replication | lacZ alpha forward mutation | yes | Sanger | G → T, A → G, C → T | (125) | |
| M1G adduct in ssDNA vector | yes | probe hybridization | G → A, G → T | NER, adduct blocks replication fork passage | (126) | |||
| human fibroblasts | MDA-treated pSP189 shuttle vector | supF reporter mutations | yes | Sanger | small indels, GC → AT, GC → TA, GC → CG | NER | (200) | |
a
Refer to main text for details of reporter systems and additional references.