Breger Kurtis, Kunkler Charlotte N, O'Leary Nathan J, Hulewicz Jacob P, Brown Jessica A
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA.
Wiley Interdiscip Rev RNA. 2023 Sep 6:e1810. doi: 10.1002/wrna.1810.
Despite the discovery of modified nucleic acids nearly 75 years ago, their biological functions are still being elucidated. N -methyladenosine (m A) is the most abundant modification in eukaryotic messenger RNA (mRNA) and has also been detected in non-coding RNAs, including long non-coding RNA, ribosomal RNA, and small nuclear RNA. In general, m A marks can alter RNA secondary structure and initiate unique RNA-protein interactions that can alter splicing, mRNA turnover, and translation, just to name a few. Although m A marks in human RNAs have been known to exist since 1974, the structures and functions of methyltransferases responsible for writing m A marks have been established only recently. Thus far, there are four confirmed human methyltransferases that catalyze the transfer of a methyl group from S-adenosylmethionine (SAM) to the N position of adenosine, producing m A: methyltransferase-like protein (METTL) 3/METTL14 complex, METTL16, METTL5, and zinc-finger CCHC-domain-containing protein 4. Though the methyltransferases have unique RNA targets, all human m A RNA methyltransferases contain a Rossmann fold with a conserved SAM-binding pocket, suggesting that they utilize a similar catalytic mechanism for methyl transfer. For each of the human m A RNA methyltransferases, we present the biological functions and links to human disease, RNA targets, catalytic and kinetic mechanisms, and macromolecular structures. We also discuss m A marks in human viruses and parasites, assigning m A marks in the transcriptome to specific methyltransferases, small molecules targeting m A methyltransferases, and the enzymes responsible for hypermodified m A marks and their biological functions in humans. Understanding m A methyltransferases is a critical steppingstone toward establishing the m A epitranscriptome and more broadly the RNome. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein-RNA Recognition RNA Interactions with Proteins and Other Molecules > RNA-Protein Complexes RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications.
尽管近75年前就发现了修饰核酸，但其生物学功能仍在不断被阐明。N-甲基腺苷（m⁶A）是真核生物信使核糖核酸（mRNA）中最丰富的修饰，在非编码RNA中也有检测到，包括长链非编码RNA、核糖体RNA和小核RNA。一般来说，m⁶A修饰可以改变RNA二级结构，并引发独特的RNA-蛋白质相互作用，进而改变剪接、mRNA周转和翻译等，仅举几例。尽管自1974年以来就已知人类RNA中存在m⁶A修饰，但负责写入m⁶A修饰的甲基转移酶的结构和功能直到最近才得以确定。到目前为止，有四种已确认的人类甲基转移酶可催化将甲基从S-腺苷甲硫氨酸（SAM）转移到腺苷的N位，生成m⁶A：甲基转移酶样蛋白（METTL）3/METTL14复合物、METTL16、METTL5和含锌指CCHC结构域蛋白4。尽管这些甲基转移酶具有独特的RNA靶点，但所有人类m⁶A RNA甲基转移酶都含有一个带有保守SAM结合口袋的Rossmann折叠结构，这表明它们利用相似的催化机制进行甲基转移。对于每一种人类m⁶A RNA甲基转移酶，我们介绍了其生物学功能、与人类疾病的联系、RNA靶点、催化和动力学机制以及大分子结构。我们还讨论了人类病毒和寄生虫中的m⁶A修饰，将转录组中的m⁶A修饰归因于特定的甲基转移酶、靶向m⁶A甲基转移酶的小分子，以及负责超修饰m⁶A修饰的酶及其在人类中的生物学功能。了解m⁶A甲基转移酶是建立m⁶A表观转录组以及更广泛的RNA组的关键垫脚石。本文分类如下：RNA与蛋白质和其他分子的相互作用>蛋白质-RNA识别；RNA与蛋白质和其他分子的相互作用>RNA-蛋白质复合物；RNA与蛋白质和其他分子的相互作用>蛋白质-RNA相互作用：功能影响。
