DNA-protein cross-link formation mediated by oxanine: A novel genotoxic mechanism of nitric oxide-induced DNA damage

Toshiaki Nakano, Hiroaki Terato, Kenjiro Asagoshi, Aya Masaoka, Miho Mukuta, Yoshihiko Ohyama, Toshinori Suzuki, Keisuke Makino, Hiroshi Ide

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Chronic inflammation is a risk factor for many human cancers, and nitric oxide (NO) produced in inflamed tissues has been proposed to cause DNA damage via nitrosation or oxidation of base moieties. Thus, NO-induced DNA damage could be relevant to carcinogenesis associated with chronic inflammation. In this report, we report a novel genotoxic mechanism of NO that involves DNA-protein cross-links (DPCs) induced by oxanine (Oxa), a major NO-induced guanine lesion. When a duplex DNA containing Oxa at the site-specific position was incubated with DNA-binding proteins such as histone, high mobility group (HMG) protein, and DNA glycosylases, DPCs were formed between Oxa and protein. The rate of DPC formation with DNA glycosylases was approximately two orders of magnitude higher than that with histone and HMG protein. Analysis of the re-activity of individual amino acids to Oxa suggested that DPC formation occurred between Oxa and side chains of lysine or arginine in the protein. A HeLa cell extract also gave rise to two major DPCs when incubated with DNA-containing Oxa. These results reveal a dual aspect of Oxa as causal damage of DPC formation and as a suicide substrate of DNA repair enzymes, both of which could pose a threat to the genetic and structural integrity of DNA, hence potentially leading to carcinogenesis.

Original languageEnglish
Pages (from-to)25264-25272
Number of pages9
JournalJournal of Biological Chemistry
Volume278
Issue number27
DOIs
Publication statusPublished - Jul 4 2003
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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