Human Ogg1, a protein involved in the repair of 8-oxoguanine, is inhibited by nitric oxide.
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.
Jaiswal
M
M
Department of Biochemistry, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
LaRusso
N F
NF
Nishioka
N
N
Nakabeppu
Y
Y
Gores
G J
GJ
D018281:Cholangiocarcinoma / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects* / Q000502:physiology; D018076:DNA, Complementary / Q000235:genetics; D043382:DNA-Formamidopyrimidine Glycosylase; D015870:Gene Expression; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D009699:N-Glycosyl Hydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology*; D015538:Nitrosation / Q000187:drug effects; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction; D011233:Precipitin Tests; D014162:Transfection; D014407:Tumor Cells, Cultured; D015032:Zinc / Q000378:metabolism
D018076:DNA, Complementary; D009566:Nitrates; D016877:Oxidants; C039642:peroxynitric acid; D009569:Nitric Oxide; C024829:8-hydroxyguanine; D006147:Guanine; D009699:N-Glycosyl Hydrolases; D043382:DNA-Formamidopyrimidine Glycosylase; D015032:Zinc