Homologous recombination contributes to the repair of acetaldehyde-induced DNA damages.

Abstract

Acetaldehyde, a chemical that can cause DNA damage and contribute to cancer, is prevalently present in our environment, e.g., in alcohol, tobacco, and food. Although aldehyde potentially promotes crosslinking reaction among biological substances including DNA, RNA, and proteins, it remains unclear what types of DNA damage are caused by acetaldehyde and how they are repaired. In this study, we examined acetaldehyde sensitivity of DNA damage-deficient cells established from human TK6 cell line. Among the mutants, mismatch repair mutants did not show a hypersensitivity to acetaldehyde, while cells deficient in base and nucleotide excision repair pathways increased its sensitivity. We found a delayed repair and hypersensitivity in homologous recombination (HR)-deficient cells but not in non-homologous end joining-deficient cells after acetaldehyde treatment. By analyzing the formation of acetaldehyde-induced RAD51 foci, which represent HR intermediates, HR-deficient cells, but not NHEJ, exhibits delayed repair of acetaldehyde-induced DNA damages, compared with wild-type. These results suggest that acetaldehyde causes complex DNA damages that requires various types of repair pathways. Interestingly, mutants deficient in TDP1 and TDP2, which are involved in the removal of protein adducts from DNA ends, exhibited hypersensitivity to acetaldehyde. the acetaldehyde sensitivity of the TDP1-/-/RAD54-/- double mutant was similar to that of each single mutant. This epistatic relationship between TDP1 and RAD54 suggests that that the removal of protein-DNA adducts generated by acetaldehyde needs to be removed for efficient repair by HR. Our study would help understand the molecular mechanism of genotoxic and mutagenic effects of acetaldehyde.