8-Oxoguanine DNA glycosylase 1 hijacked by nucleoprotein conceals guanine oxidation in respiratory syncytial virus RNA

Respiratory Syncytial Virus (RSV), alongside other prominent respiratory RNA viruses such as influenza and SARS-CoV-2, significantly contributes to the global incidence of respiratory tract infections. These pathogens prompt the production of reactive oxygen species (ROS), which play a crucial role in the onset and progression of respiratory diseases. However, the strategies by which viral RNA manages ROS-induced base oxidation are not well understood. Here we uncover that 8-oxo-7,8-dihydroguanine (8-oxoGua) is not merely an incidental byproduct of ROS activity but serves as a strategic adaptation of RSV RNA during replication within host cells. Through RNA immunoprecipitation and next-generation sequencing, we discovered that 8-oxoguanine DNA glycosylase 1 (OGG1) binding sites are predominantly found in the RSV antigenome, especially within guanine-rich areas. Further investigation revealed that viral ribonucleoprotein complexes specifically hijack OGG1. Crucially, our findings show that inhibiting OGG1's ability to recognize 8-oxoGua leads to a substantial reduction in RSV progeny production. Our results underscore the viral replication machinery's adaptation to oxidative challenges, pointing to the inhibition of OGG1's reading function as a potential novel strategy for antiviral intervention. RSV nucleocapsid immunoprecipitation RNA-sequencing (RNA-seq) for OGG1 in Human Small Airway Epithelial Cells (hSAECs).