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m6A/m6Am RNA 甲基转移酶结构的全面综述

A comprehensive review of m6A/m6Am RNA methyltransferase structures.

机构信息

Expression Génétique Microbienne, UMR 8261, CNRS, Université de Paris, Institut de Biologie Physico-Chimique (IBPC), 75005 Paris, France.

出版信息

Nucleic Acids Res. 2021 Jul 21;49(13):7239-7255. doi: 10.1093/nar/gkab378.

Abstract

Gene expression is regulated at many levels including co- or post-transcriptionally, where chemical modifications are added to RNA on riboses and bases. Expression control via RNA modifications has been termed 'epitranscriptomics' to keep with the related 'epigenomics' for DNA modification. One such RNA modification is the N6-methylation found on adenosine (m6A) and 2'-O-methyladenosine (m6Am) in most types of RNA. The N6-methylation can affect the fold, stability, degradation and cellular interaction(s) of the modified RNA, implicating it in processes such as splicing, translation, export and decay. The multiple roles played by this modification explains why m6A misregulation is connected to multiple human cancers. The m6A/m6Am writer enzymes are RNA methyltransferases (MTases). Structures are available for functionally characterized m6A RNA MTases from human (m6A mRNA, m6A snRNA, m6A rRNA and m6Am mRNA MTases), zebrafish (m6Am mRNA MTase) and bacteria (m6A rRNA MTase). For each of these MTases, we describe their overall domain organization, the active site architecture and the substrate binding. We identify areas that remain to be investigated, propose yet unexplored routes for structural characterization of MTase:substrate complexes, and highlight common structural elements that should be described for future m6A/m6Am RNA MTase structures.

摘要

基因表达在多个水平上受到调控,包括转录共调控或转录后调控,其中在核糖和碱基上添加化学修饰。通过 RNA 修饰进行的表达控制被称为“表观转录组学”,以与相关的 DNA 修饰“表观基因组学”保持一致。RNA 修饰之一是在大多数类型的 RNA 上发现的腺苷(m6A)和 2'-O-甲基腺苷(m6Am)上的 N6-甲基化。N6-甲基化可以影响修饰 RNA 的折叠、稳定性、降解和细胞相互作用,使其参与剪接、翻译、输出和降解等过程。这种修饰所起的多种作用解释了为什么 m6A 调节异常与多种人类癌症有关。m6A/m6Am 书写酶是 RNA 甲基转移酶(MTases)。来自人类(m6A mRNA、m6A snRNA、m6A rRNA 和 m6Am mRNA MTases)、斑马鱼(m6Am mRNA MTase)和细菌(m6A rRNA MTase)的功能表征的 m6A RNA MTase 结构可用。对于每一种 MTase,我们描述了它们的整体结构域组织、活性位点结构和底物结合。我们确定了仍有待研究的领域,提出了尚未探索的 MTase:底物复合物结构表征途径,并强调了未来 m6A/m6Am RNA MTase 结构应该描述的常见结构元素。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/aabd/8287941/08163328f9ea/gkab378fig1.jpg

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