YTHDF2 destabilizes m6A-containing RNA through direct recruitment of the CCR4–NOT deadenylase complex

Abstract Methylation at the N 6 position of adenosine (m 6 A) is the most abundant RNA modification within protein-coding and long noncoding RNAs in eukaryotes and is a reversible process with important biological functions. YT521-B homology domain family (YTHDF) proteins are the readers of m 6 A, the binding of which results in the alteration of the translation efficiency and stability of m 6 A-containing RNAs. However, the mechanism by which YTHDF proteins cause the degradation of m 6 A-containing RNAs is poorly understood. Here we report that m 6 A-containing RNAs exhibit accelerated deadenylation that is mediated by the CCR4–NOT deadenylase complex. We further show that YTHDF2 recruits the CCR4–NOT complex through a direct interaction between the YTHDF2 N-terminal region and the SH domain of the CNOT1 subunit, and that this recruitment is essential for the deadenylation of m 6 A-containing RNAs by CAF1 and CCR4. Therefore, we have uncovered the mechanism of YTHDF2-mediated degradation of m 6 A-containing RNAs in mammalian cells.