Cap-specific terminal N6-methylation of RNA by an RNA polymerase II-associated methyltransferase
Cap-specific terminal N6-methylation of RNA by an RNA polymerase II-associated methyltransferase
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DOI：
10.1126/science.aav0080
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发表时间：
2019-01-11
期刊：
影响因子：
56.9
通讯作者：
Suzuki, Tsutomu
中科院分区：
文献类型：
--
作者：
Akichika, Shinichiro;Hirano, Seiichi;Suzuki, Tsutomu
N-6-甲基腺苷（m（6）A）是信使RNA（mRNAs）的主要修饰物，在RNA代谢和功能中起着重要作用。除了内部m（6）A，N-6，2 '-O-二甲基腺苷（m（6）Am）存在于脊椎动物中加帽mRNA的转录起始核苷酸处。然而，其生物起源和功能作用仍然难以捉摸。使用反向遗传学方法，我们鉴定了PCIF 1，一种与RNA聚合酶II的丝氨酸-5-磷酸化羧基末端结构域相互作用的因子，作为负责m（6）Am的N-6-甲基化的帽特异性腺苷甲基转移酶（CAPAM）。CAPAM与底物复合物的晶体结构揭示了帽特异性m（6）A形成的分子基础。全转录组分析显示，m（6）Am的N-6-甲基化促进加帽mRNA的翻译。因此，帽特异性m（6）A写入器促进从m（6）Am开始的mRNA的翻译。
N-6-methyladenosine (m(6)A), a major modification of messenger RNAs (mRNAs), plays critical roles in RNA metabolism and function. In addition to the internal m(6)A, N-6, 2'-O-dimethyladenosine (m(6)Am) is present at the transcription start nucleotide of capped mRNAs in vertebrates. However, its biogenesis and functional role remain elusive. Using a reverse genetics approach, we identified PCIF1, a factor that interacts with the serine-5-phosphorylated carboxyl-terminal domain of RNA polymerase II, as a cap-specific adenosine methyltransferase (CAPAM) responsible for N-6-methylation of m(6)Am. The crystal structure of CAPAM in complex with substrates revealed the molecular basis of cap-specific m(6)A formation. A transcriptome-wide analysis revealed that N-6-methylation of m(6)Am promotes the translation of capped mRNAs. Thus, a cap-specific m(6)A writer promotes translation of mRNAs starting from m(6)Am.