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

Abstract

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.

Genomic 8-oxoguanine modulates gene transcription independent of its repair by DNA glycosylases OGG1 and MUTYH

“…Several recent studies suggested a role for OG as an epigenetic-like mark. Stress-induced accumulation of OG and recognition by OGG1 in promoter regions was shown to regulate gene expression of specific genes (8,9). In addition, apurinic (AP) sites generated by excision of OG activates gene transcription, which has been demonstrated for vascular endothelial growth factor ( VEGF ), endonuclease III-like protein 1 ( NTHL1 ) (10) and sirtuin 1 ( SIRT1 ) genes (11).…”

Substrate-specific binding of 8-oxoguanine DNA glycosylase 1 (OGG1) reprograms mucosal adaptations to chronic airway injury

“…In a recent study by Pan et al. ( 57 ), small airway epithelial cells in culture could phenotypically convert to spindle-shaped mesenchymal cells, by a mechanism that involved OGG1-mediated molecular reprogramming in response to TGFβ exposure ( Figure 3 ). Cellular plasticity in EMT requires transcriptional networks mediated by key transcription factors, of particular importance is SMAD3 in the SMAD complex.…”

“…In the chromatin context, genome-wide binding of OGG1 is also mapped to illustrate stimulus-driven association of OGG1 with NFκB ( 56 ). Another study using chromatin immunoprecipitation (ChIP) assay shows that OGG1 reading 8-oxoGua accommodates phosphorylated SMADs complex binding to SMAD binding elements of pro-fibrotic genes, such α-SMA, fibronectin (FN) and collagen (COL), thereby facilitating gene activation ( 57 ). The physiological significance is striking, as OGG1 reading 8-oxoGua is temporally utilized to skew the repair function to trigger transcription, thereby repurposing OGG1 for the immune response.…”

“…This also imposes supraphysiological mechanical forces on the epithelial cells. Interestingly, mechanical stress resultant from inflammatory exudates in lower airways generates oxidative DNA damage, as detected by the presence of 8-oxoGua ( 57 , 83 ), suggesting that 8-oxoGua is actively generated by TGFβ signaling. For epithelial repopulation, integrin αvβ8-mediated activation of TGFβ inhibits airway epithelial cell proliferation ( 84 ).…”

OGG1 as an Epigenetic Reader Affects NFκB: What This Means for Cancer

“…Additionally, it was shown that DNA-bound OGG1 at 8-oxoGua interacted with mitogen-and stress-activated kinase 1, which phosphorylates NFκB/RelA at serine 276, inducing expression of innate cytokines and chemokines [ 46 ]. A recent study documented that OGG1 at 8-oxoGua in the context of chromatin recruited phosphorylated SMAD2/3 complex and NFκB to their cognate binding sequence located in promoters of tissue remodeling genes including alpha-smooth muscle actin (α-SMA), collagen (COL), and fibronectin (FN) for excessive gene expression [ 41 , 47 ]. Another recent study revealed that Myc oncogene binding to the E-box promoter recognition sequence required OGG1 under oxidative stress conditions [ 48 ].…”