YTHDF2 destabilizes m ⁶A-containing RNA through direct recruitment of the CCR4–NOT deadenylase complex

Abstract

Methylation at the N6 position of adenosine (m ⁶A) 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 ⁶A, the binding of which results in the alteration of the translation efficiency and stability of m ⁶A-containing RNAs. However, the mechanism by which YTHDF proteins cause the degradation of m ⁶A-containing RNAs is poorly understood. Here we report that m ⁶A-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 ⁶A-containing RNAs by CAF1 and CCR4. Therefore, we have uncovered the mechanism of YTHDF2-mediated degradation of m ⁶A-containing RNAs in mammalian cells.

Abstract

The YTHDF family of proteins are able to bind and regulate the stability of methylated N6 RNA. Here the authors show that this decreased m ⁶A RNA stability is mediated by direct recruitment of the CCR4–NOT deadenylase complex through YTHDF proteins.