Modulation of circRNA Metabolism by mA Modification.

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.