Differential repair of polycyclic aromatic hydrocarbon DNA adducts from an actively transcribed gene |
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| Authors: | Qing Zhong Shantu Amin Philip Lazarus Thomas E Spratt |
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| Institution: | 1. Department of Biochemistry & Molecular Biology, Pennsylvania State University, 500 University Dr, Hershey, PA 17033, USA;2. Department of Pharmacology, Pennsylvania State University, 500 University Dr, Hershey, PA 17033, USA;3. Chemical Carcinogenesis and Chemoprevention Program, Penn State Cancer Institute, 500 University Dr, Hershey, PA 17033, USA;4. Molecular Epidemiology and Cancer Control Program, Penn State Cancer Institute, 500 University Dr, Hershey, PA 17033, USA;1. Division of Oral Pathology and Maxillofacial Radiology, Department of Dentistry, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan;2. School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;3. Oral and Maxillofacial Imaging Center, Kaohsiung Medical University, Kaohsiung, Taiwan;4. Department of Dentistry, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan;5. Department of Physiology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;1. Department of Bromatology, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland;2. Division of Rehabilitation, Department of Physiotherapy, 2nd Medical Faculty, Medical University of Warsaw, Poland;1. New York Medical College, Department of Pathology, Valhalla, NY, 10595, USA;2. Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, 88379 Biberach an der Riss, Germany;1. Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Japan;2. Food Safety Commission, Cabinet Office, Government of Japan, Japan;3. Department of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, Japan;1. Patuxent Wildlife Research Center, US Geological Survey, c/o BARC-East, Building 308, 10300 Baltimore Avenue, Beltsville, MD 20705, USA;2. Department of Environment and Aquatic Animal Health, Virginia Institute of Marine Science, Gloucester Point, VA 23062, USA;1. Risk Benefit Assessment Department, National Food Agency, Uppsala, Sweden;2. Infectious Diseases, Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden;3. Food Data Division, National Food Agency, Uppsala, Sweden |
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| Abstract: | Polycyclic aromatic hydrocarbons (PAHs) are carcinogens with varying potencies. These compounds are metabolized to diol epoxides that react to form DNA adducts. Nucleotide excision repair is a critical cellular defense against these bulky DNA adducts which, if not repaired, can lead to mutations and the initiation of cancer. The structural features of the PAH-adducts play a role in differential repair of these adducts by the global genomic repair subpathway of nucleotide excision repair. DNA adducts derived from the PAHs containing bay-regions are repaired more rapidly than adducts derived from PAHs containing fjord-regions. We have employed the host cell reactivation assay to examine the rate of repair of these adducts in an actively transcribing gene. The pGL3 plasmid containing a luciferase gene was damaged with diol epoxides of benzoa]pyrene (Ba]P-DE), dibenzoa,l]pyrene (DBa,l]P-DE), benzog]chrysene (Bg]Ch-DE), and benzoc]phenanthrene (Bc]Ph-DE). The plasmids were transfected into B-lymphocytes with normal repair capacity as well as lymphocytes derived from patients with the XP-A, XP-C and CS-B syndromes. We found that XPA cells were able to transcribe slowly past Bg]Ch-adducts but not the other PAHs. Using the amount of luciferase produced as a measure of DNA repair, we found that the relative rates of repair in the actively transcribing luciferase gene was Ba]P-DE > DBa,l]P-DE, Bg]Ch-DE, >Bc]Ph-DE in repair proficient and XP-C cells. These results indicate that the abilities to transcribe past and to repair the PAH adducts are dependent on different structural features of the DNA adducts. |
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