State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China.
CAS-Shanghai Science Research Center, Chinese Academy of Sciences, Shanghai 201204, China.
Nat Commun. 2016 Aug 25;7:12626. doi: 10.1038/ncomms12626.
Methylation at the N6 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.
腺苷 N6 位的甲基化（m(6)A）是真核生物中蛋白编码和长非编码 RNA 中最丰富的 RNA 修饰，是一个具有重要生物学功能的可逆过程。YT521-B 同源结构域家族（YTHDF）蛋白是 m(6)A 的阅读器，其结合导致 m(6)A 含有 RNA 的翻译效率和稳定性发生改变。然而，YTHDF 蛋白导致 m(6)A 含有 RNA 降解的机制尚不清楚。在这里，我们报告 m(6)A 含有 RNA 表现出加速的去腺苷酸化，这是由 CCR4-NOT 脱腺苷酸酶复合物介导的。我们进一步表明，YTHDF2 通过 YTHDF2 N 端区域与 CNOT1 亚基的 SH 结构域之间的直接相互作用，招募 CCR4-NOT 复合物，并且这种募集对于 CAF1 和 CCR4 对 m(6)A 含有 RNA 的去腺苷酸化是必不可少的。因此，我们揭示了 YTHDF2 介导的哺乳动物细胞中 m(6)A 含有 RNA 降解的机制。
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