Genotoxicity of Aldehyde-Induced DNA Damage

Aldehydes such as formaldehyde and acetaldehyde arise from both endogenous metabolism and environmental exposure. Their electrophilic carbonyl group reacts with DNA to form a variety of lesions, including mono-adducts, interstrand crosslinks, intrastrand crosslinks and DNA–protein crosslinks. These lesions impede replication fork progression and transcription, leading to replication stress, chromosomal aberrations and mutagenesis. Cellular defence relies on detoxifying enzymes—principally aldehyde dehydrogenases—and coordinated DNA repair pathways. Key repair processes include nucleotide excision repair, transcription-coupled repair and homologous recombination, often supported by specialised nucleases to excise bulky adducts. When detoxification or repair is compromised, as in ALDH2 or ADH5 deficiency or in carriers of DNA repair gene mutations, aldehyde-induced genotoxicity contributes to bone marrow failure, neurodegeneration and cancer predisposition.

Research from Nature Portfolio

Recent studies have defined critical regulators and lesion structures. A genome-wide CRISPR–Cas9 screen identified the exonuclease EXO1 as a central factor in processing formaldehyde-induced DNA–protein crosslinks and interstrand crosslinks. EXO1 is recruited to stalled replication forks, limits fork degradation and functions alongside the Fanconi anaemia pathway to maintain genomic stability. In parallel, chemical characterisation of acetaldehyde damage revealed a reversible GG intrastrand crosslink between adjacent guanines. This lesion exists in equilibrium with unmodified bases and provides a molecular explanation for the mutagenic signature associated with alcohol metabolism and environmental aldehyde exposure.

Genotoxicity of Aldehyde-Induced DNA Damage publication trend

The graph below shows the total number of articles in genotoxicity of aldehyde-induced dna damage across all publications each year (not limited to Nature Index journals).

Technical terms

DNA–protein crosslink (DPC): A covalent bond between DNA and proteins that obstructs replication and transcription machinery.

Interstrand crosslink (ICL): A covalent linkage joining complementary DNA strands, preventing strand separation.

Replication fork: The Y-shaped structure formed during DNA synthesis where parental strands are unwound and copied.

Nucleotide excision repair (NER): A versatile pathway that recognises and removes bulky, helix-distorting DNA lesions.

Transcription-coupled repair (TCR): A sub-pathway of NER that specifically targets lesions on the transcribed strand of active genes.

Reactive aldehyde: An electrophilic organic compound containing a carbonyl group that can form covalent adducts with biomolecules.

References

1. A CRISPR-Cas9 screen identifies EXO1 as a formaldehyde resistance gene. Nature Communications (2023).
2. Acetaldehyde forms covalent GG intrastrand crosslinks in DNA. Scientific Reports (2019).
3. Distinct DNA repair mechanisms prevent formaldehyde toxicity during development, reproduction and aging. Nucleic Acids Research (2024).
4. Two Aldehyde Clearance Systems Are Essential to Prevent Lethal Formaldehyde Accumulation in Mice and Humans. Molecular Cell (2020).
5. A Class of Environmental and Endogenous Toxins Induces BRCA2 Haploinsufficiency and Genome Instability. Cell (2017).