Modulation of circRNA Metabolism by m6A Modification

N⁶-methyladenosine (m⁶A) 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 m⁶A 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 m⁶As 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 m⁶A exons to undergo back-splicing. Finally, because circ-ZNF609 displays the ability to be translated, we show that m⁶A modifications, through recognition by YTHDF3 and eIF4G2, modulate its translation.