α,β-Unsaturated Aldehyde-Induced Delays in Nucleotide Excision Repair and the Contribution of Reactive Oxygen Species

Abstract

Aldehydes are widespread environmental and industrial compounds to which humans are frequently exposed. Despite their significant health risk, the mechanisms underlying aldehyde toxicity are poorly understand. We recently demonstrated that cigarette sidestream smoke (CSS) inhibited nucleotide excision repair (NER), and this was attributed to aldehydes in CSS. In the present study, we examined the influence of saturated and unsaturated aldehydes on NER. The human keratinocyte cell line, HaCaT, was treated with aldehydes and then exposed to UVB. Saturated aldehydes did not show toxicity, whereas α,β-unsaturated aldehydes caused cell death, which was markedly enhanced by UV exposure. The speed of NER was examined by the detection of pyrimidine (6-4) pyrimidone photoproducts (6-4PPs) using ELISA and local UV irradiation assay. The repair of 6-4PPs was markedly reduced by α,β-unsaturated aldehydes, but not by saturated aldehydes, and this was attributed to a delay in the recruitment of repair proteins (TFIIH and XPG) to DNA damage sites. Reactive oxygen species (ROS) were produced after a treatment with α,β-unsaturated aldehydes, and hydrogen peroxide (HO) inhibited the repair of 6-4PPs, similar to α,β-unsaturated aldehydes. HO inhibited the accumulation of XPA and XPG at DNA damage sites, whereas TFIIH showed the same recruitment with or without HO. These results suggest that an exposure to α,β-unsaturated aldehydes, not saturated aldehydes inhibits NER by delaying the recruitment of NER proteins to DNA damage sites, and α,β-unsaturated aldehyde-induced ROS production may partially play a role in this process.

Oncorequisite role of an aldehyde dehydrogenase in the pathogenesis of T-cell acute lymphoblastic leukemia

“…On the other hand, previous studies provided evidences that ALDH family proteins help alleviate intracellular ROS (36)(37)(38). The underlying mechanism is attributable to their capability in clearage of cellular aldehydes, which are known as ROS inducer (39)(40)(41). Thus, we next measured the total level of intracellular ROS after depletion of ALDH1A2 using three different settings (sgRNA, shRNA and smallmolecule inhibitor) in Jurkat cells.…”