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(American Journal of Pathology. 2006;169:1328-1342.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.051280

Contrasting Genome-Wide Distribution of 8-Hydroxyguanine and Acrolein-Modified Adenine during Oxidative Stress-Induced Renal Carcinogenesis

Shinya Akatsuka^*, Than Tin Aung^*, Khokon Kumar Dutta^*, Li Jiang^*, Wen-Hua Lee^*, Yu-Ting Liu^*, Janice Onuki^*, Tomoyuki Shirase^*, Kyoko Yamasaki^*, Hirotomo Ochi, Yuji Naito, Toshikazu Yoshikawa^¶, Hiroshi Kasai^||, Yohei Tominaga^**, Kunihiko Sakumi^**, Yusaku Nakabeppu^**, Yoshichika Kawai, Koji Uchida, Aiichi Yamasaki, Tatsuaki Tsuruyama^*, Yoshihiro Yamada^* and Shinya Toyokuni^*

From the Department of Pathology and Biology of Diseases,^* Graduate School of Medicine, and the Department of Mathematics, Graduate School of Science, Kyoto University, Kyoto; Japan Institute for the Control of Aging, Fukuroi; Medical Proteomics, and Inflammation and Immunology,^¶ Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto; Department of Environmental Oncology,|| University of Occupational and Environmental Health, Kita-Kyushu; Department of Immunobiology and Neuroscience,^** Division of Neurofunctional Genomics, Medical Institute of Bioregulation, Kyushu University, Fukuoka; the Laboratory of Food and Biodynamics, Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya, Japan; and Laboratory of Biochemistry and Biophysics, Butanten Institute, São Paulo, São Paulo, Brazil

Oxidative stress is a persistent threat to the genome and is associated with major causes of human mortality, including cancer, atherosclerosis, and aging. Here we established a method to generate libraries of genomic DNA fragments containing oxidatively modified bases by using specific monoclonal antibodies to immunoprecipitate enzyme-digested genome DNA. We applied this technique to two different base modifications, 8-hydroxyguanine and 1,N⁶-propanoadenine (acrotein-Ade), in a ferric nitrilotriacetate-induced murine renal carcinogenesis model. Renal cortical genomic DNA derived from 10- to 12-week-old male C57BL/6 mice, of untreated control or 6 hours after intraperitoneal injection of 3 mg iron/kg ferric nitrilotriacetate, was enzyme digested, immunoprecipitated, cloned, and mapped to each chromosome. The results revealed that distribution of the two modified bases was not random but differed in terms of chromosomes, gene size, and expression, which could be partially explained by chromosomal territory. In the wild-type mice, low GC content areas were more likely to harbor the two modified bases. Knockout of OGG1, a repair enzyme for genomic 8-hydroxyguanine, increased the amounts of acrolein-Ade as determined by quantitative polymerase chain reaction analyses. This versatile technique would introduce a novel research area as a high-throughput screening method for critical genomic loci under oxidative stress.

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