Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, Rome, Italy.
Groningen Biomolecular Sciences and Biotechnology Institute, Groningen, the Netherlands.
Cell Rep. 2020 May 12;31(6):107641. doi: 10.1016/j.celrep.2020.107641.
N-methyladenosine (mA) is an RNA modification well-known for its contribution to different processes controlling RNA metabolism, including splicing, stability, and translation of mRNA. Conversely, the role of mA on the biogenesis and function of circular RNAs (circRNAs) has yet to be addressed. circRNAs belong to a class of covalently closed transcripts produced via a back-splicing reaction whereby a downstream 5' splice donor site fuses to an upstream 3' splice acceptor site. Starting from circ-ZNF609 as a study case, we discover that specific mAs control its accumulation and that METTL3 and YTHDC1 are required to direct the back-splicing reaction. This feature is shared with other circRNAs because we find a significant direct correlation among METTL3 requirement, YTHDC1 binding, and the ability of mA exons to undergo back-splicing. Finally, because circ-ZNF609 displays the ability to be translated, we show that mA modifications, through recognition by YTHDF3 and eIF4G2, modulate its translation.
N6-甲基腺苷（m6A）是一种 RNA 修饰，其在调控 RNA 代谢的不同过程中起着重要作用，包括剪接、mRNA 的稳定性和翻译。相反，m6A 对环状 RNA（circRNA）的生物发生和功能的作用尚未得到解决。circRNA 属于一类通过反式剪接反应产生的共价闭合转录本，其中下游 5' 剪接供体位点与上游 3' 剪接受体位点融合。以 circ-ZNF609 为研究案例，我们发现特定的 m6A 控制其积累，并且 METTL3 和 YTHDC1 是指导反式剪接反应所必需的。这一特征与其他 circRNA 共享，因为我们发现 METTL3 需求、YTHDC1 结合和 m6A 外显子发生反式剪接的能力之间存在显著的直接相关性。最后，由于 circ-ZNF609 具有被翻译的能力，我们表明 m6A 修饰通过 YTHDF3 和 eIF4G2 的识别来调节其翻译。
