title: Effect of carcinogenic acrolein on DNA repair and mutagenic susceptibility.
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.
authors.affiliation: Department of Environmental Medicine, New York University School of Medicine, New York, New York 10987, USA.
authors.forename: Hsiang-Tsui
authors.initials: HT
authors.lastname: Wang
authors.forename: Yu
authors.initials: Y
authors.lastname: Hu
authors.forename: Dan
authors.initials: D
authors.lastname: Tong
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.forename: Liya
authors.initials: L
authors.lastname: Gu
authors.forename: Xue-Ru
authors.initials: XR
authors.lastname: Wu
authors.forename: Fung-Lung
authors.initials: FL
authors.lastname: Chung
authors.forename: Guo-Min
authors.initials: GM
authors.lastname: Li
authors.forename: Moon-shong
authors.initials: MS
authors.lastname: Tang
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000737:chemistry; D000171:Acrolein / Q000494:pharmacology*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D055745:Bronchioles / Q000166:cytology; D002273:Carcinogens / Q000494:pharmacology*; D002478:Cells, Cultured; D018736:DNA Adducts / Q000378:metabolism*; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects*; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008168:Lung / Q000166:cytology; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D009153:Mutagens / Q000737:chemistry / Q000494:pharmacology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D010957:Plasmids / Q000737:chemistry / Q000528:radiation effects; D020545:Respiratory Mucosa / Q000166:cytology; D014466:Ultraviolet Rays; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002273:Carcinogens; D018736:DNA Adducts; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009153:Mutagens; D009687:Nuclear Proteins; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; C086984:XPC protein, human; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D000171:Acrolein; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D045643:DNA Repair Enzymes