The study investigates the mechanism by which YTHDF2, a reader of m6A (N6-methyladenosine) modification, destabilizes m6A-containing RNAs. It is found that m6A-containing RNAs exhibit accelerated deadenylation, which is mediated by the CCR4-NOT deadenylase complex. YTHDF2 recruits the CCR4-NOT complex through a direct interaction between its N-terminal region and the SH domain of the CNOT1 subunit, which is essential for the deadenylation of m6A-containing RNAs by CAF1 and CCR4. This mechanism explains how YTHDF2-mediated degradation of m6A-containing RNAs occurs in mammalian cells.The study investigates the mechanism by which YTHDF2, a reader of m6A (N6-methyladenosine) modification, destabilizes m6A-containing RNAs. It is found that m6A-containing RNAs exhibit accelerated deadenylation, which is mediated by the CCR4-NOT deadenylase complex. YTHDF2 recruits the CCR4-NOT complex through a direct interaction between its N-terminal region and the SH domain of the CNOT1 subunit, which is essential for the deadenylation of m6A-containing RNAs by CAF1 and CCR4. This mechanism explains how YTHDF2-mediated degradation of m6A-containing RNAs occurs in mammalian cells.