Translatable Circular RNAs are Degraded Via Nonsense-mediated mRNA Decay

Endogenous circular RNAs (circRNAs) are predominantly generated by a back-splicing process. Due to their lacking 5' and 3' termini, circRNA degradation is exclusively dependent on endoribonucleolytic cleavage. In addition, translation occurring on circRNAs depends solely on internal ribosome entry site (IRES) or IRES-like features, such as an exon junction complex (EJC) deposited after back-splicing. However, the potential relationship between the translatability and stability of circRNAs has yet to be explored. Here, we demonstrate that translatable circRNAs can be subject to canonical EJC-dependent nonsense-mediated mRNA decay (NMD), a well-known mRNA surveillance mechanism, as long as circRNAs contain EJC(s) downstream of a translation termination codon. We find that the NMD of translatable circRNAs involves UPF1 and the NMD-specific endoribonuclease SMG6. This distinct pathway is termed NMD-like circRNA decay (NCD). The differences in factor requirements between canonical EJC-dependent NMD and NCD lead to variations in RNA regulation under cellular stress conditions. Our observations provide an additional layer in the molecular regulation of circRNA dynamics.