Structural and Virus Regulatory Insights Into Avian N6-Methyladenosine (m6A) Machinery
Structural and Virus Regulatory Insights Into Avian N6-Methyladenosine (m6A) Machinery
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DOI：
10.3389/fcell.2020.00543
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发表时间：
2020-07-15
影响因子：
5.5
通讯作者：
Munir, Muhammad
中科院分区：
文献类型：
--
作者：
Bayoumi, Mahmoud;Rohaim, Mohammed A.;Munir, Muhammad
腺苷（m6 A）的N6位添加甲基是最常见的转录后RNA修饰，它调节RNA代谢的大多数步骤，包括剪接，稳定性，翻译，核输出和RNA结构。除了细胞RNA，m6 A修饰也在病毒RNA上检测到。最近的一系列研究已经证明了m6 A在病毒-宿主相互作用中的关键作用;然而，m6 A细胞机制仅在有限的哺乳动物物种中表征。在此，我们的目标是提出全面的进化见解，主要m6 A作家，擦除器和读者，并绘制鸟类和哺乳动物m6 A相关的机制之间的比较结构分析。染色体规模上的比较共线性显示，大多数的m6 A相关基因被发现少同线，即使在鸟类物种。鸟类m6 A擦除器的遗传分析显示了一个独特的系统发育聚类相比，哺乳动物的直系同源物和共享一个弱的百分比（55%）的同一性与哺乳动物物种低的同一性百分比（55%）。通过同义结构突变维持不同哺乳动物物种之间的整体比较三维（3D）结构分析。与橡皮擦不同的是，在鸡中，YTHDC 1的YTH结构域中的芳香笼和胃L3的MTD结构域中的两个关键环的活性位点中的推定的3D结构表现出结构改变。结合silicoinvestigations，流感病毒显着下调基因的转录m6 A作家和橡皮擦，而m6 A读者适度调节鸡成纤维细胞。鉴于这些发现，未来的详细的生化和晶体学研究是必要的，以确定m6 A机制在调节鸟类病毒和细胞RNA代谢的作用。
The addition of a methyl group to the N6 position of adenosine (m6A) is the most common posttranscriptional RNA modification, and it regulates most steps of RNA metabolism including splicing, stability, translation, nuclear-export, and RNA structures. Besides cellular RNA, m6A modifications have also been detected on viral RNA. A range of recent studies have demonstrated the crucial roles of m6A in the virus-host interactions; however, m6A cellular machineries are only characterized in limited mammalian species. Herein, we aim to present comprehensive evolutionary insights into major m6A writers, erasers, and readers and draw a comparative structural analysis between avian and mammalian m6A-associated machineries. The comparative collinearity on the chromosomal scale revealed that the majority of m6A-related genes were found less syntenic even among avian species. Genetic analysis of avian m6A erasers revealed a distinct phylogenetic clustering compared to mammalian orthologs and shared a weak percent (55%) identity with mammalian species with low identity percentage (55%). The overall comparative three-dimensional (3D) structure analyses among different mammalian species were maintained through synonymous structural mutations. Unlike erasers, the putative 3D structures in the active sites as for the aromatic cage in YTH-domain of YTHDC1 and two pivotal loops in MTD-domains in METTL3 exhibited structural alterations in chicken. In conjunction within silicoinvestigations, influenza viruses significantly downregulated gene the transcription of m6A writers and erasers, whereas m6A readers were moderately regulated in chicken fibroblasts. In light of these findings, future detailed biochemical and crystallographic studies are warranted to define the roles of m6A machinery in regulating both viral and cellular RNA metabolism in avian species.