Circular RNAs trigger nonsense-mediated mRNA decay

Circular RNAs (circRNAs) are covalently closed single-stranded RNAs produced predominantly through a back-splicing process. They play regulatory roles in various biological and physiological processes; however, the molecular mechanisms by which circRNAs operate remain unclear. Herein, we demonstrate that circRNAs facilitate rapid mRNA degradation through RNA-RNA interactions between circRNAs and the 3' untranslated regions (3' UTRs) of mRNAs. This interaction positions the exon-junction complexes (EJCs), deposited onto circRNAs by back-splicing, near the 3' UTRs of the mRNAs, thereby leading to EJC-dependent nonsense-mediated mRNA decay (NMD), a process we describe as circRNA-induced NMD (circNMD). Our transcriptomic analysis reveals hundreds of potential circNMD candidates, and the biological importance of circNMD in cellular apoptosis is validated. We also demonstrate that exogenously expressed circRNAs designed to interact with the 3' UTRs of endogenous mRNAs significantly downregulate the mRNA levels. Collectively, our observations provide compelling molecular evidence for circNMD and its potential therapeutic application in selective mRNA downregulation.