8-oxoguanine DNA glycosylase-1 augments proinflammatory gene expression by facilitating the recruitment of site-specific transcription factors.
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.
Department of Microbiology and Immunology, University of Texas Medical Branch at Galveston, Galveston, TX 77555;
Xueqing
X
Ba
Attila
A
Bacsi
Jixian
J
Luo
Leopoldo
L
Aguilera-Aguirre
Xianlu
X
Zeng
Zsolt
Z
Radak
Allan R
AR
Brasier
Istvan
I
Boldogh
D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000276:immunology*; D045647:DNA Glycosylases / Q000235:genetics / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D020218:Response Elements / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
D016207:Cytokines; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; C479058:oxoguanine glycosylase 1, human