2024年3月13日

大学院生の山﨑航輔君、笹沼博之副参事研究員の論文『Homologous recombination contributes to the repair of acetaldehyde-induced DNA damages 』がCell Cycle誌(IF 4.7)への掲載が許可されました。

この論文では、アセトアルデヒドにより誘導されるDNA損傷が、相同組換え依存的修復システムで修復されることを示しました。

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 reactions 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 the acetaldehyde sensitivity of DNA damage-deficient cells established from the human TK6 cell line. Among the mutants, mismatch repair mutants did not show hypersensitivity to acetaldehyde, while cells deficient in base and nucleotide excision repair pathways increased their sensitivity. We found a delayed repair and hypersensitivity in homologous recombination (HR)-deficient cells but not in nonhomologous 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, exhibit delayed repair of acetaldehyde-induced DNA damages, compared with wild-type. These results suggest that acetaldehyde causes complex DNA damages that require 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 double mutant deficient in both TDP1 and RAD54 was similar to that of each single mutant. This epistatic relationship between TDP1 and RAD54 suggests 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 the genotoxic and mutagenic effects of acetaldehyde.

KEY WORDS: homologous recombination, acetaldehyde, DNA-protein adducts