Fig. 3: Epitranscriptional roles of o⁸G.

a Defective protein synthesis induced by o⁸G. ROS-induced o⁸G in mRNA lowers its coding capacity and causes ribosome stalling, thus advertently producing abortive proteins. ROS can oxidize the free ribonucleotide o⁸GTP, which can be incorporated during RNA transcription and cause U > o⁸G mutation in mRNA. b Ribosome-based quality control of o⁸G-mRNAs. o⁸G-induced ribosome stalling in mRNA triggers NGD, of which the complex consists of DOM34 and Cue2, cleaves o⁸G-mRNAs, and induces degradation using decay machinery, comprising exosomes and Xrn1. c o⁸G-mRNA degradation mediated by ribonucleases and RBPs. PNPase binds o⁸G and degrades o⁸G-containing RNAs. APE1 binds o⁸G or o⁸G-derived abasic sites to recognize oxidized RNAs and triggers cleavage for degradation. YB-1 interacts with o⁸G and induces RNA decay or stabilization. d o⁸G modulates signaling pathways by interacting with RBPs and G proteins. PCBP1 and PCBP2 recognize heavily oxidized RNAs by binding to two o⁸Gs sites, leading to the opposite effects; PCBP1 activates but PCBP2 inhibits apoptotic signaling (upper panel). ROS induce oxidation of free ribonucleotide (o⁸GTP), which binds to G protein and modulates the function in signal transduction (lower panel). e o⁸G-induced global repression of translation. Under ROS production, o⁸G modification, which predominantly occurs in rRNA and tRNA, induces decay and cleavage of oxidized rRNA and tRNA, resulting in the global suppression of translation. f o⁸G regulates the functions of noncoding RNAs. Position-specific o⁸G in the seed region of miRNAs redirects its target recognition via o⁸G•A base pairing, resulting in the induction of pathophysiological changes (e.g., cardiac hypertrophy induced by o⁸G-miR-1; upper left panel). Position-specific o⁸G in rRNA may regulate translational activity (upper right panel). Oxidative stress-induced cleavage of tRNA may be regulated by o⁸G, generating tsRNAs as regulators of the stress response. o⁸G modification in tRNA may result in changes in other modifications, which lead to alterations in tRNA function (lower panel).