Potential role of 8-oxoguanine DNA glycosylase 1 as a STAT1 coactivator in endotoxin-induced inflammatory response.
Human 8-oxoguanine DNA glycosylase 1 (OGG1) is the major DNA repair enzyme that plays a key role in excision of oxidative damaged DNA bases such as 8-oxoguainine (8-oxoG). Recent studies suggest another function of OGG1, namely that it may be involved in the endotoxin- or oxidative stress-induced inflammatory response. In this study, we investigated the role of OGG1 in the inflammatory response. OGG1 expression is increased in the organs of endotoxin-induced or myelin oligodendrocyte glycoprotein (MOG)-immunized mice and immune cells, resulting in induction of the expression of pro-inflammatory mediators at the transcriptional levels. Biochemical studies showed that signal transducer and activator of transcription 1 (STAT1) plays a key role in endotoxin-induced OGG1 expression and inflammatory response. STAT1 regulates the transcriptional activity of OGG1 through recruiting and binding to the gamma-interferon activation site (GAS) motif of the OGG1 promoter region, and chromatin remodeling by acetylation and dimethylation of lysine-14 and -4 residues of histone H3. In addition, OGG1 acts as a STAT1 coactivator and has transcriptional activity in the presence of endotoxin. The data presented here identifies a novel mechanism, and may provide new therapeutic strategies for the treatment of endotoxin-mediated inflammatory diseases.
Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea.
Hong Sook
HS
Kim
Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea; Biomedical Science Project (BK21PLUS), Seoul National University College of Medicine, Seoul, Republic of Korea.
Byung-Hak
BH
Kim
Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Rehabilitation Medicine, CHA University, Gyeonggi, Republic of Korea.
Joo Eun
JE
Jung
Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea; AmorePacific R&D Center, Gyeonggi, Republic of Korea.
Chang Seok
CS
Lee
Department of Microbiology and Immunology, Yonsei University College of Medicine, Seoul, Republic of Korea.
Hyun Gyu
HG
Lee
Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Medicinal Bioconvergence Research Center, Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Republic of Korea; Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul, Republic of Korea.
Jung Weon
JW
Lee
National Research Center for Dementia and Department of Biomedical Science, Chosun University, Gwangju, Republic of Korea.
Kun Ho
KH
Lee
Department of Pharmacology, School of Medicine and the Research Center for Proteineous Materials, Chosun University, Gwangju, Republic of Korea.
Ho Jin
HJ
You
Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea; Lee Gil Ya Cancer & Diabetes Institute, Gachon University, Incheon, Republic of Korea.
Myung-Hee
MH
Chung
Department of Pharmacology, Seoul National University College of Medicine, Seoul, Republic of Korea; Biomedical Science Project (BK21PLUS), Seoul National University College of Medicine, Seoul, Republic of Korea; Neuro-Immune Information Storage Network Research Center, Seoul National University College of Medicine, Republic of Korea; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul, Republic of Korea. Electronic address: sangkyu@snu.ac.kr.
Sang-Kyu
SK
Ye
D000818:Animals; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D045647:DNA Glycosylases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair / Q000235:genetics; D004731:Endotoxins / Q000633:toxicity; D005786:Gene Expression Regulation; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D011401:Promoter Regions, Genetic; D050794:STAT1 Transcription Factor / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics*
D004731:Endotoxins; D063308:Myelin-Oligodendrocyte Glycoprotein; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; C024829:8-hydroxyguanine; D006147:Guanine; D007371:Interferon-gamma; D045647:DNA Glycosylases; C479058:oxoguanine glycosylase 1, human
Coactivator; Endotoxin; Inflammation; OGG1; STAT1