Effect of Carcinogenic Acrolein on DNA Repair and Mutagenic Susceptibility

• Published in: The Journal of biological chemistry 2012-04, Vol.287 (15), p.12379-12386
• Main Authors: Wang, Hsiang-Tsui, Hu, Yu, Tong, Dan, Huang, Jian, Gu, Liya, Wu, Xue-Ru, Chung, Fung-Lung, Li, Guo-Min, Tang, Moon-shong
• Format: Article
• Language: English
• Subjects: 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide - chemistry; Acrolein; Acrolein - pharmacology; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Adenosine Triphosphatases - genetics; Adenosine Triphosphatases - metabolism; Base Sequence; BPDE-DNA Damage; Bronchioles - cytology; Carcinogens - pharmacology; Cells, Cultured; DNA Adducts - metabolism; DNA and Chromosomes; DNA Damage; DNA Glycosylases - genetics; DNA Glycosylases - metabolism; DNA Mismatch Repair; DNA Nucleotide Excision Repair; DNA Repair; DNA Repair - drug effects; DNA Repair Enzymes - genetics; DNA Repair Enzymes - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Fibroblasts - drug effects; Fibroblasts - metabolism; Gene Expression - drug effects; Humans; Lung - cytology; Lung Cancer; Mismatch Repair Endonuclease PMS2; Mutagenesis; Mutagens - chemistry; Mutagens - pharmacology; MutL Protein Homolog 1; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oxidation-Reduction; Plasmids - chemistry; Plasmids - radiation effects; Respiratory Mucosa - cytology; Ultraviolet Rays; Xeroderma Pigmentosum Group A Protein - genetics; Xeroderma Pigmentosum Group A Protein - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M111.329623

Acrolein (Acr), a ubiquitous environmental contaminant, is a human carcinogen. Acr can react with DNA to form mutagenic α- and γ-hydroxy-1, N2-cyclic propano-2′-deoxyguanosine adducts (α-OH-Acr-dG and γ-OH-Acr-dG). We demonstrate here that Acr-dG adducts can be efficiently repaired by the nucleotide excision repair (NER) pathway in normal human bronchial epithelia (NHBE) and lung fibroblasts (NHLF). However, the same adducts were poorly processed in cell lysates isolated from Acr-treated NHBE and NHLF, suggesting that Acr inhibits NER. In addition, we show that Acr treatment also inhibits base excision repair and mismatch repair. Although Acr does not change the expression of XPA, XPC, hOGG1, PMS2 or MLH1 genes, it causes a reduction of XPA, XPC, hOGG1, PMS2, and MLH1 proteins; this effect, however, can be neutralized by the proteasome inhibitor MG132. Acr treatment further enhances both bulky and oxidative DNA damage-induced mutagenesis. These results indicate that Acr not only damages DNA but can also modify DNA repair proteins and further causes degradation of these modified repair proteins. We propose that these two detrimental effects contribute to Acr mutagenicity and carcinogenicity. Background: Acrolein is highly reactive and abundant in tobacco smoke. Results: Acrolein induces DNA damage, inhibits excision repair and mismatch repair, causes repair protein degradation, and enhances mutagenesis. Conclusion: Acrolein induces DNA damage and inhibits DNA repair that causes mutagenesis and initiates carcinogenesis. Significance: This is the first demonstration that acrolein inhibits DNA repair pathways by induction of repair protein degradation.