title: The role of base excision repair genes OGG1, APN1 and APN2 in benzo[a]pyrene-7,8-dione induced p53 mutagenesis.
abstract: Lung cancer is primarily caused by exposure to tobacco smoke. Tobacco smoke contains numerous carcinogens, including polycyclic aromatic hydrocarbons (PAH). The most common PAH studied is benzo[a]pyrene (B[a]P). B[a]P is metabolically activated through multiple routes, one of which is catalyzed by aldo-keto reductase (AKR) to B[a]P-7,8-dione (BPQ). BPQ undergoes a futile redox cycle in the presence of NADPH to generate reactive oxygen species (ROS). ROS, in turn, damages DNA. Studies with a yeast p53 mutagenesis system found that the generation of ROS by PAH o-quinones may contribute to lung carcinogenesis because of similarities between the patterns (types of mutations) and spectra (location of mutations) and those seen in lung cancer. The patterns were dominated by G to T transversions, and the spectra in the experimental system have mutations at lung cancer hotspots. To address repair mechanisms that are responsible for BPQ induced damage we observed the effect of mutating two DNA repair genes OGG1 and APE1 (APN1 in yeast) and tested them in a yeast reporter system for p53 mutagenesis. There was an increase in both the mutant frequency and the number of G:C/T:A transversions in p53 treated with BPQ in ogg1 yeast but not in apn1 yeast. Knocking out APN2 increased mutagenesis in the apn1 cells. In addition, we did not find a strand bias on p53 treated with BPQ in ogg1 yeast. These studies suggest that Ogg1 is involved in repairing the oxidative damage caused by BPQ, Apn1 and Apn2 have redundant functions and that the stand bias seen in lung cancer may not be due to impaired repair of oxidative lesions.
authors.affiliation: Department of Pharmacology, Centers for Excellence in Environmental Toxicology and Cancer Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6084, USA.
authors.forename: Zahidur
authors.initials: Z
authors.lastname: Abedin
authors.forename: Melissa
authors.initials: M
authors.lastname: Louis-Juste
authors.forename: Melissa
authors.initials: M
authors.lastname: Stangl
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Field
mesh_terms: D001564:Benzo(a)pyrene / Q000633:toxicity*; D004249:DNA Damage; D045647:DNA Glycosylases / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics*; D004706:Endodeoxyribonucleases / Q000235:genetics*; D016158:Genes, p53; D016296:Mutagenesis; D009153:Mutagens / Q000737:chemistry* / Q000633:toxicity*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*
chemical_list: D009153:Mutagens; D029701:Saccharomyces cerevisiae Proteins; D001564:Benzo(a)pyrene; D004706:Endodeoxyribonucleases; C083274:Apn1 protein, S cerevisiae; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human; C468953:APN2 protein, S cerevisiae; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D045643:DNA Repair Enzymes