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Title: 8-oxoguanine DNA glycosylase-1 augments proinflammatory gene expression by facilitating the recruitment of site-specific transcription factors.

Authors: Ba, Xueqing; Bacsi, Attila; Luo, Jixian; Aguilera-Aguirre, Leopoldo; Zeng, Xianlu; Radak, Zsolt; Brasier, Allan R; Boldogh, Istvan

Published In J Immunol, (2014 Mar 01)

Abstract: Among the insidious DNA base lesions, 8-oxo-7,8-dihydroguanine (8-oxoG) is one of the most abundant, a lesion that arises through the attack by reactive oxygen species on guanine, especially when located in cis-regulatory elements. 8-oxoG is repaired by the 8-oxoguanine glycosylase 1 (OGG1)-initiated DNA base excision repair pathway. In this study, we investigated whether 8-oxoG repair by OGG1 in promoter regions is compatible with a prompt gene expression and a host innate immune response. For this purpose, we used a mouse model of airway inflammation, supplemented with cell cultures, chromatin immunoprecipitation, small interfering RNA knockdown, real-time PCR, and comet and reporter transcription assays. Our data show that exposure of cells to TNF-α altered cellular redox, increased the 8-oxoG level in DNA, recruited OGG1 to promoter sequences, and transiently inhibited base excision repair of 8-oxoG. Promoter-associated OGG1 then enhanced NF-κB/RelA binding to cis-elements and facilitated recruitment of specificity protein 1, transcription initiation factor II-D, and p-RNA polymerase II, resulting in the rapid expression of chemokines/cytokines and inflammatory cell accumulation in mouse airways. Small interfering RNA depletion of OGG1 or prevention of guanine oxidation significantly decreased TNF-α-induced inflammatory responses. Taken together, these results show that nonproductive binding of OGG1 to 8-oxoG in promoter sequences could be an epigenetic mechanism to modulate gene expression for a prompt innate immune response.

PubMed ID: 24489103 Exiting the NIEHS site

MeSH Terms: Animals; Cytokines/genetics; Cytokines/immunology*; DNA Glycosylases/genetics; DNA Glycosylases/immunology*; Female; Gene Expression Regulation/genetics; Gene Expression Regulation/immunology*; HEK293 Cells; Humans; Immunity, Innate*; Inflammation/genetics; Inflammation/immunology; Inflammation/pathology; Mice; Mice, Inbred BALB C; Mice, Knockout; Response Elements/immunology*; Transcription Factors/genetics; Transcription Factors/immunology*; Tumor Necrosis Factor-alpha/genetics; Tumor Necrosis Factor-alpha/immunology

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