Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Science. 2019 Jan 11;363(6423). doi: 10.1126/science.aav0080. Epub 2018 Nov 22.
-methyladenosine (mA), a major modification of messenger RNAs (mRNAs), plays critical roles in RNA metabolism and function. In addition to the internal mA, , 2'--dimethyladenosine (mAm) 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 -methylation of mAm. The crystal structure of CAPAM in complex with substrates revealed the molecular basis of cap-specific mA formation. A transcriptome-wide analysis revealed that -methylation of mAm promotes the translation of capped mRNAs. Thus, a cap-specific mA writer promotes translation of mRNAs starting from mAm.
-甲基腺苷（mA）是信使 RNA（mRNA）的主要修饰物，在 RNA 代谢和功能中发挥关键作用。除了内部 mA 外，脊椎动物中帽状 mRNA 的转录起始核苷酸处存在 2′--二甲氧基腺苷（mAm）。然而，其生物发生和功能作用仍然难以捉摸。使用反向遗传学方法，我们鉴定出 PCIF1 是一种与 RNA 聚合酶 II 的 S5 磷酸化羧基末端结构域相互作用的因子，是负责 mAm 甲基化的帽特异性腺苷甲基转移酶（CAPAM）。CAPAM 与底物结合的晶体结构揭示了帽特异性 mA 形成的分子基础。全转录组分析显示，mAm 的甲基化促进了帽状 mRNA 的翻译。因此，帽特异性 mA 写入器促进了从 mAm 起始的 mRNA 翻译。
