Deficiencies In Mismatch Repair Proteins Induce Elevated Levels Of Acrolein-Derived 1,N-2-Propanodeoxyguanosine And Apoptosis In Human Colon Cancer Cells Treated With Acrolein

Acrolein-derived 1,N 2 -propanodeoxyguanosine (Acr-dG) is a ubiquitous DNA modification in vivo that may play a role in carcinogenesis. It can be formed when DNA reacts with acrolein in environmental pollutants, such as cigarette smoking and oil combustion, and from endogenous source through oxidation of polyunsaturated fatty acids (PUFAs). We have previously demonstrated that the formation of Acr-dG at a threshold level is linked to apoptosis in cells treated with PUFAs under oxidative condition, suggesting a potential role of Acr-dG in the apoptosis induced by PUFAs, especially ω-3 PUFAs. Acr-dG can be repaired by the nucleotide excision repair (NER) pathway. To examine whether mismatch repair (MMR) pathway is also involved in the repair of Acr-dG, we treated MLH1-deficient HCT116 cell and its isogenic MLH1-proficient HCT116+ch3 cell with acrolein. The Acr-dG levels and apoptosis both were higher in HCT116 cells compared to HCT116+ch3 cells. To further study the role of MMR proteins in the repair of Acr-dG, either MLH1 or MSH2 was knocked down in HCT116+ch3 cells. The results showed that the levels of Acr-dG and apoptosis induction were both significantly higher in the knockdown cells than the cells transfected with control siRNA. The levels of p-ATM and γ-H2AX were also increased to a greater extent in HCT116 cells than HCT116+ch3 cells, and in the MLH1 and MSH2 knockdown cells than the control cells when treated with acrolein at the doses that induce higher levels of Acr-dG. This study shows that MMR proteins, MLH1 and MSH2, are involved in the repair of Acr-dG. The results also suggest that Acr-dG may cause double-strand breaks which lead to apoptosis. Whether MMR acts as an independent repair pathway for Acr-dG or MMR proteins cross-talk and interact with other DNA repair pathways, such as NER, is under investigation. (Supported by NCI grant CA43159) Citation Format: Jishen Pan, Zhuoli Xuan, Marcin Dyba, Yongwei Zhang, Ying Fu, Rabindra Roy, Louis M. Weiner, Fung-Lung Chung. Deficiencies in mismatch repair proteins induce elevated levels of acrolein-derived 1, N 2 -propanodeoxyguanosine and apoptosis in human colon cancer cells treated with acrolein. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5362. doi:10.1158/1538-7445.AM2014-5362