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Human Ogg1, a Protein Involved in the Repair of 8-Oxoguanine, Is Inhibited by Nitric Oxide¹

Department of Biochemistry, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan 812-8582 [N. N., Y. N.]; and Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatobiology, Mayo Clinic/Foundation/Medical School, Rochester, Minnesota 55905 [M. J., N. F. L., G. J. G.]

NO-mediated inhibition of base excision DNA repair may potentiate oxidativeDNA damage in cells and could be relevant to carcinogenesis associated with chronic inflammation. Because 8-oxoguanine, a ubiquitous oxidative DNA lesion, is repaired predominantly by human 8-oxoguanine glycosylase (hOgg1), our aim was to determine whether NO directly inhibits its repair activity. Neither induction of NO-generating enzyme inducible NO synthase nor treatment with S-nitroso-N-acetyl-D-L-pencillamine altered expression of hOgg1 in a human cholangiocarcinoma cell line (KMBC). In contrast, both treatments completely inhibited activity of hOgg1 immunoprecipitated from KMBC cells overexpressing hOgg1 and in a cell-free system. Both NO and peroxynitrite were capable of inhibiting hOgg1 activity. Inhibition of hOgg1 protein was characterized by formation of S-nitrosothiol adducts and loss/ejection of zinc ions. Our data indicate that NO, an inflammatory mediator, directly inhibits a key base excision repair enzyme (hOgg1) responsible for base excision repair of 8-oxoguanine. These data support the concept that NO-mediated inhibition of DNA contributes to the mutagenic environment of chronic inflammation.

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