8-Oxoguanine targeted by 8-oxoguanine DNA glycosylase 1 (OGG1) is central to fibrogenic gene activation upon lung injury

Lang Pan, Wenjing Hao, Yaoyao Xue, Ke Wang, Xu Zheng, Jixian Luo, Xueqing Ba, Yang Xiang, Xiaoqun Qin, Jesper Bergwik, Lloyd Tanner, Arne Egesten, Allan Brasier, Istvan Boldogh

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Reactive oxygen species (ROS) are implicated in epithelial cell-state transition and deposition of extracellular matrix upon airway injury. Of the many cellular targets of ROS, oxidative DNA modification is a major driving signal. However, the role of oxidative DNA damage in modulation profibrotic processes has not been fully delineated. Herein, we report that oxidative DNA base lesions, 8-oxoG, complexed with 8-oxoguanine DNA glycosylase 1 (OGG1) functions as a pioneer factor, contributing to transcriptional reprogramming within airway epithelial cells. We show that TGFβ1-induced ROS increased 8-oxoG levels in open chromatin, dynamically reconfigure the chromatin state. OGG1 complexed with 8-oxoG recruits transcription factors, including phosphorylated SMAD3, to pro-fibrotic gene promoters thereby facilitating gene activation. Moreover, 8-oxoG levels are elevated in lungs of mice subjected to TGFβ1-induced injury. Pharmacologic targeting of OGG1 with the selective small molecule inhibitor of 8-oxoG binding, TH5487, abrogates fibrotic gene expression and remodeling in this model. Collectively, our study implicates that 8-oxoG substrate-specific binding by OGG1 is a central modulator of transcriptional regulation in response to tissue repair.

Original languageEnglish (US)
Pages (from-to)1087-1102
Number of pages16
JournalNucleic acids research
Issue number3
StatePublished - Feb 22 2023

ASJC Scopus subject areas

  • Genetics


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