title: Oxidized Guanine Base Lesions Function in 8-Oxoguanine DNA Glycosylase-1-mediated Epigenetic Regulation of Nuclear Factor κB-driven Gene Expression.
abstract: A large percentage of redox-responsive gene promoters contain evolutionarily conserved guanine-rich clusters; guanines are the bases most susceptible to oxidative modification(s). Consequently, 7,8-dihydro-8-oxoguanine (8-oxoG) is one of the most abundant base lesions in promoters and is primarily repaired via the 8-oxoguanine DNA glycosylase-1 (OOG1)-initiated base excision repair pathway. In view of a prompt cellular response to oxidative challenge, we hypothesized that the 8-oxoG lesion and the cognate repair protein OGG1 are utilized in transcriptional gene activation. Here, we document TNFα-induced enrichment of both 8-oxoG and OGG1 in promoters of pro-inflammatory genes, which precedes interaction of NF-κB with its DNA-binding motif. OGG1 bound to 8-oxoG upstream from the NF-κB motif increased its DNA occupancy by promoting an on-rate of both homodimeric and heterodimeric forms of NF-κB. OGG1 depletion decreased both NF-κB binding and gene expression, whereas Nei-like glycosylase-1 and -2 had a marginal effect. These results are the first to document a novel paradigm wherein the DNA repair protein OGG1 bound to its substrate is coupled to DNA occupancy of NF-κB and functions in epigenetic regulation of gene expression.
authors.affiliation: From the Departments of Microbiology and Immunology and.|the Key Laboratory of Molecular Epigenetics, Ministry of Education, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China, and.
authors.forename: Lang
authors.initials: L
authors.lastname: Pan
authors.affiliation: From the Departments of Microbiology and Immunology and.
authors.forename: Bing
authors.identifier: http://orcid.org/0000-0002-8371-3182
authors.initials: B
authors.lastname: Zhu
authors.affiliation: the Key Laboratory of Molecular Epigenetics, Ministry of Education, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China, and.
authors.forename: Wenjing
authors.initials: W
authors.lastname: Hao
authors.affiliation: the Key Laboratory of Molecular Epigenetics, Ministry of Education, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China, and.
authors.forename: Xianlu
authors.identifier: http://orcid.org/0000-0002-2655-4197
authors.initials: X
authors.lastname: Zeng
authors.affiliation: From the Departments of Microbiology and Immunology and.
authors.forename: Spiros A
authors.identifier: http://orcid.org/0000-0001-6245-3863
authors.initials: SA
authors.lastname: Vlahopoulos
authors.affiliation: Medicine, and.|the Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, Texas 77555.
authors.forename: Tapas K
authors.identifier: http://orcid.org/0000-0002-4587-687X
authors.initials: TK
authors.lastname: Hazra
authors.affiliation: the Department of Radiation Oncology and Neurology, Methodist Research Institute, Houston, Texas 77030.
authors.forename: Muralidhar L
authors.identifier: http://orcid.org/0000-0001-7333-8123
authors.initials: ML
authors.lastname: Hegde
authors.affiliation: From the Departments of Microbiology and Immunology and.
authors.forename: Zsolt
authors.identifier: http://orcid.org/0000-0003-1297-6804
authors.initials: Z
authors.lastname: Radak
authors.affiliation: From the Departments of Microbiology and Immunology and.
authors.forename: Attila
authors.identifier: http://orcid.org/0000-0002-2311-2975
authors.initials: A
authors.lastname: Bacsi
authors.affiliation: Medicine, and.|the Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, Texas 77555.
authors.forename: Allan R
authors.identifier: http://orcid.org/0000-0002-5012-4090
authors.initials: AR
authors.lastname: Brasier
authors.affiliation: From the Departments of Microbiology and Immunology and baxq755@nenu.edu.cn.|the Key Laboratory of Molecular Epigenetics, Ministry of Education, Institute of Genetics and Cytology, Northeast Normal University, Changchun 130024, China, and.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Ba
authors.affiliation: From the Departments of Microbiology and Immunology and sboldogh@utmb.edu.|the Sealy Center for Molecular Medicine, University of Texas Medical Branch, Galveston, Texas 77555.
authors.forename: Istvan
authors.identifier: http://orcid.org/0000-0002-0088-1130
authors.initials: I
authors.lastname: Boldogh
mesh_terms: D000818:Animals; D045647:DNA Glycosylases / Q000096:biosynthesis* / Q000235:genetics; D004260:DNA Repair; D044127:Epigenesis, Genetic; D015971:Gene Expression Regulation, Enzymologic; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; C024829:8-hydroxyguanine; D006147:Guanine; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; C479058:oxoguanine glycosylase 1, human
keywords: 8-oxoguanine (8-oxoG); 8-oxoguanine glycosylase (OGG1); NF-κB transcription factor; promoter; reactive oxygen species (ROS)