Circular RNAs trigger nonsense-mediated mRNA decay. Boo et al.

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.

环状RNA（circRNAs）是一种通过回拼接过程主要产生的共价闭合单链RNA。它们在各种生物学和生理过程中扮演着调控角色；然而，circRNA运作的分子机制尚不明确。本研究中，我们揭示了circRNA通过环状RNA与mRNA的3'非翻译区（3'UTRs）之间的RNA-RNA相互作用，促进mRNA的快速降解。这种相互作用将回拼接至环状RNA上的外显子连接复合物（EJCs）定位在mRNA的3'UTRs附近，从而引发EJC依赖的无效RNA介导的mRNA降解（NMD），我们将其描述为环状RNA诱导的NMD（circNMD）。我们的转录组分析揭示了数百个潜在的circNMD候选者，并且circNMD在细胞凋亡中的生物学重要性得到了验证。此外，我们亦证明，外源表达的旨在与内源mRNA的3'UTRs相互作用的环状RNA，能够显著下调mRNA水平。综上所述，我们的观察结果为circNMD及其在选择性mRNA下调中的潜在治疗应用提供了令人信服的分子证据。