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 TsuruyamaYoshihiro Yamada, Shinya Toyokuni

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)

Abstract

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,N 6-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.

Original languageEnglish
Pages (from-to)1328-1342
Number of pages15
JournalAmerican Journal of Pathology
Volume169
Issue number4
DOIs
Publication statusPublished - Oct 2006

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

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