YTHDF2 destabilizes m6A containing RNA through direct recruitment of the CCR4 NOT deadenylase complex
Methylation at the N6 position of adenosine (m6A) 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 m6A, the binding of which results in the alteration of the translation efficiency and stability of m6A containing RNAs. However, the mechanism by which YTHDF proteins cause the degradation of m6A containing RNAs is poorly understood. Here we report that m6A 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 m6A containing RNAs by CAF1 and CCR4. Therefore, we have uncovered the mechanism of YTHDF2 mediated degradation of m6A containing RNAs in mammalian cells.
Nature communications