Innate inflammation induced by the 8-oxoguanine DNA glycosylase-1-KRAS-NF-κB pathway

Leopoldo Aguilera-Aguirre, Attila Bacsi, Zsolt Radak, Tapas K. Hazra, Sankar Mitra, Sanjiv Sur, Allan R. Brasier, Xueqing Ba, Istvan Boldogh

Research output: Contribution to journalArticle

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Abstract

8-Oxoguanine-DNA glycosylase-1 (OGG1) is the primary enzyme for repairing 7,8-dihydro-8-oxoguanine (8-oxoG) via the DNA base excision repair pathway (OGG1-BER). Accumulation of 8-oxoG in the genomic DNA leads to genetic instability and carcinogenesis and is thought to contribute to the worsening of various inflammatory and disease processes. However, the disease mechanism is unknown. In this study, we proposed that the mechanistic link between OGG1-BER and proinflammatory gene expression is OGG1's guanine nucleotide exchange factor activity, acquired after interaction with the 8-oxoG base and consequent activation of the small GTPase RAS. To test this hypothesis, we used BALB/c mice expressing or deficient in OGG1 in their airway epithelium and various molecular biological approaches, including active RAS pulldown, reporter and Comet assays, small interfering RNA-mediated depletion of gene expression, quantitative RT-PCR, and immunoblotting. We report that the OGG1-intiated repair of oxidatively damaged DNA is a prerequisite for GDP→GTP exchange, KRAS-GTP-driven signaling via MAP kinases and PI3 kinases and mitogen-stress-related kinase-1 for NF-κB activation, proinflammatory chemokine/cytokine expression, and inflammatory cell recruitment to the airways. Mice deficient in OGG1-BER showed significantly decreased immune responses, whereas a lack of other Nei-like DNA glycosylases (i.e., NEIL1 and NEIL2) had no significant effect. These data unveil a previously unidentified role of OGG1-driven DNA BER in the generation of endogenous signals for inflammation in the innate signaling pathway.

Original languageEnglish
Pages (from-to)4643-4653
Number of pages11
JournalJournal of Immunology
Volume193
Issue number9
DOIs
Publication statusPublished - 2014 Nov 1
Externally publishedYes

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DNA Glycosylases
Inflammation
DNA
Guanine Nucleotide Exchange Factors
Gene Expression
Comet Assay
Monomeric GTP-Binding Proteins
8-hydroxyguanine
Mitogen-Activated Protein Kinase Kinases
Guanosine Triphosphate
Phosphatidylinositol 3-Kinases
Mitogens
Chemokines
Immunoblotting
DNA Repair
Small Interfering RNA
Carcinogenesis
Phosphotransferases
Epithelium
Cytokines

ASJC Scopus subject areas

  • Immunology

Cite this

Aguilera-Aguirre, L., Bacsi, A., Radak, Z., Hazra, T. K., Mitra, S., Sur, S., ... Boldogh, I. (2014). Innate inflammation induced by the 8-oxoguanine DNA glycosylase-1-KRAS-NF-κB pathway. Journal of Immunology, 193(9), 4643-4653. https://doi.org/10.4049/jimmunol.1401625

Innate inflammation induced by the 8-oxoguanine DNA glycosylase-1-KRAS-NF-κB pathway. / Aguilera-Aguirre, Leopoldo; Bacsi, Attila; Radak, Zsolt; Hazra, Tapas K.; Mitra, Sankar; Sur, Sanjiv; Brasier, Allan R.; Ba, Xueqing; Boldogh, Istvan.

In: Journal of Immunology, Vol. 193, No. 9, 01.11.2014, p. 4643-4653.

Research output: Contribution to journalArticle

Aguilera-Aguirre, L, Bacsi, A, Radak, Z, Hazra, TK, Mitra, S, Sur, S, Brasier, AR, Ba, X & Boldogh, I 2014, 'Innate inflammation induced by the 8-oxoguanine DNA glycosylase-1-KRAS-NF-κB pathway', Journal of Immunology, vol. 193, no. 9, pp. 4643-4653. https://doi.org/10.4049/jimmunol.1401625
Aguilera-Aguirre L, Bacsi A, Radak Z, Hazra TK, Mitra S, Sur S et al. Innate inflammation induced by the 8-oxoguanine DNA glycosylase-1-KRAS-NF-κB pathway. Journal of Immunology. 2014 Nov 1;193(9):4643-4653. https://doi.org/10.4049/jimmunol.1401625
Aguilera-Aguirre, Leopoldo ; Bacsi, Attila ; Radak, Zsolt ; Hazra, Tapas K. ; Mitra, Sankar ; Sur, Sanjiv ; Brasier, Allan R. ; Ba, Xueqing ; Boldogh, Istvan. / Innate inflammation induced by the 8-oxoguanine DNA glycosylase-1-KRAS-NF-κB pathway. In: Journal of Immunology. 2014 ; Vol. 193, No. 9. pp. 4643-4653.
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