8-Oxoguanine DNA glycosylase1 repairactome: transcriptional reprogramming in radiation-induced lung injury

PURPOSE: This narrative review aims to elucidate the interconnections between ionizing radiation (IR)-induced oxidative base modification(s) and gene expression reprogramming that promote tissue repair, driving lung fibrosis and ultimately resulting in life-threatening organ dysfunction with limited therapeutic options. CONCLUSIONS: IR introduces diverse chemical modifications into chromatin, affecting both histones and DNA, both directly or indirectly through reactive oxygen and nitrogen species. Among DNA bases, guanine -an electron-rich heterocycle-is the most susceptible to oxidation, primarily forming 8-oxo-7,8-dihydroguanine (8-oxoGua). Long regarded solely as a mutagenic biomarker of oxidative stress, 8-oxoGua is now recognized as an epigenetic-like mark that serves as a platform for anchoring 8-oxoguanine DNA glycosylase 1 (OGG1), that interacts with both chromatin remodelers and transcription factors, thus, promoting essential transcription initiation complex assembly. In this capacity, the OGG1 repairactome acts as a signaling hub rather than merely an initiator of base excision repair and is essential for transcriptional reprogramming toward controlled and/or unrestrained inflammatory and profibrotic programs. These include those mediated by TGF-β/SMAD signaling that drives myofibroblast differentiation and extracellular matrix deposition in promoting tissue repair. Notably, pharmacological inhibition of OGG1 repairactome formation markedly attenuates pulmonary pathologies induced by the radiomimetic agent bleomycin or by TGF-β1, thereby preserving and improving lung function in experimental models.