8-Oxoguanine DNA glycosylase-1 augments proinflammatory gene expression by facilitating the recruitment of site-specific transcription factors

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

Research output: Contribution to journalArticle

45 Citations (Scopus)

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-A 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-kB/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-A-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.

Original languageEnglish (US)
Pages (from-to)2384-2394
Number of pages11
JournalJournal of Immunology
Volume192
Issue number5
DOIs
StatePublished - Mar 1 2014

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DNA Glycosylases
Transcription Factors
Gene Expression
Guanine
Innate Immunity
DNA Repair
Small Interfering RNA
DNA
Sp1 Transcription Factor
Peptide Initiation Factors
RNA Polymerase II
NF-kappa B
Chromatin Immunoprecipitation
8-hydroxyguanine
Chemokines
Genetic Promoter Regions
Epigenomics
Oxidation-Reduction
Real-Time Polymerase Chain Reaction
Reactive Oxygen Species

ASJC Scopus subject areas

  • Immunology

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8-Oxoguanine DNA glycosylase-1 augments proinflammatory gene expression by facilitating the recruitment of site-specific transcription factors. / Ba, Xueqing; Bacsi, Attila; Luo, Jixian; Aguilera-Aguirre, Leopoldo; Zeng, Xianlu; Radak, Zsolt; Brasier, Allan R.; Boldogh, Istvan.

In: Journal of Immunology, Vol. 192, No. 5, 01.03.2014, p. 2384-2394.

Research output: Contribution to journalArticle

Ba, Xueqing ; Bacsi, Attila ; Luo, Jixian ; Aguilera-Aguirre, Leopoldo ; Zeng, Xianlu ; Radak, Zsolt ; Brasier, Allan R. ; Boldogh, Istvan. / 8-Oxoguanine DNA glycosylase-1 augments proinflammatory gene expression by facilitating the recruitment of site-specific transcription factors. In: Journal of Immunology. 2014 ; Vol. 192, No. 5. pp. 2384-2394.
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AB - 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-A 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-kB/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-A-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.

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