Title: Effect of carcinogenic acrolein on DNA repair and mutagenic susceptibility.
Authors: Wang, Hsiang-Tsui; Hu, Yu; Tong, Dan; Huang, Jian; Gu, Liya; Wu, Xue-Ru; Chung, Fung-Lung; Li, Guo-Min; Tang, Moon-shong
Published In J Biol Chem, (2012 Apr 06)
Abstract: Acrolein (Acr), a ubiquitous environmental contaminant, is a human carcinogen. Acr can react with DNA to form mutagenic α- and γ-hydroxy-1, N(2)-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.
PubMed ID: 22275365
MeSH Terms: 7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide/chemistry; Acrolein/pharmacology*; Adaptor Proteins, Signal Transducing/genetics; Adaptor Proteins, Signal Transducing/metabolism; Adenosine Triphosphatases/genetics; Adenosine Triphosphatases/metabolism; Base Sequence; Bronchioles/cytology; Carcinogens/pharmacology*; Cells, Cultured; DNA Adducts/metabolism*; DNA Glycosylases/genetics; DNA Glycosylases/metabolism; DNA Repair Enzymes/genetics; DNA Repair Enzymes/metabolism; DNA Repair/drug effects*; 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; Mismatch Repair Endonuclease PMS2; MutL Protein Homolog 1; Mutagens/chemistry; Mutagens/pharmacology*; 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