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

TLDR

m6A is the most common RNA modification in eukaryotes, read by YTHDF proteins, yet the mechanism by which these readers trigger RNA degradation remains unclear. We show that YTHDF2 directly recruits the CCR4–NOT complex through its N‑terminal region binding CNOT1, driving deadenylation of m6A‑modified RNAs.

Abstract

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.