Kurtis Breger, Charlotte N Kunkler, Nathan J O'Leary, Jacob P Hulewicz, Jessica A Brown
{"title":"鬼才作者透露:人类 N6 -甲基腺苷 RNA 甲基转移酶的结构和功能。","authors":"Kurtis Breger, Charlotte N Kunkler, Nathan J O'Leary, Jacob P Hulewicz, Jessica A Brown","doi":"10.1002/wrna.1810","DOIUrl":null,"url":null,"abstract":"<p><p>Despite the discovery of modified nucleic acids nearly 75 years ago, their biological functions are still being elucidated. N<sup>6</sup> -methyladenosine (m<sup>6</sup> 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<sup>6</sup> 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<sup>6</sup> A marks in human RNAs have been known to exist since 1974, the structures and functions of methyltransferases responsible for writing m<sup>6</sup> 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<sup>6</sup> position of adenosine, producing m<sup>6</sup> 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<sup>6</sup> 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<sup>6</sup> 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<sup>6</sup> A marks in human viruses and parasites, assigning m<sup>6</sup> A marks in the transcriptome to specific methyltransferases, small molecules targeting m<sup>6</sup> A methyltransferases, and the enzymes responsible for hypermodified m<sup>6</sup> A marks and their biological functions in humans. Understanding m<sup>6</sup> A methyltransferases is a critical steppingstone toward establishing the m<sup>6</sup> 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.</p>","PeriodicalId":23886,"journal":{"name":"Wiley Interdisciplinary Reviews: RNA","volume":null,"pages":null},"PeriodicalIF":6.4000,"publicationDate":"2023-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10915109/pdf/","citationCount":"0","resultStr":"{\"title\":\"Ghost authors revealed: The structure and function of human N<sup>6</sup> -methyladenosine RNA methyltransferases.\",\"authors\":\"Kurtis Breger, Charlotte N Kunkler, Nathan J O'Leary, Jacob P Hulewicz, Jessica A Brown\",\"doi\":\"10.1002/wrna.1810\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Despite the discovery of modified nucleic acids nearly 75 years ago, their biological functions are still being elucidated. N<sup>6</sup> -methyladenosine (m<sup>6</sup> 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<sup>6</sup> 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<sup>6</sup> A marks in human RNAs have been known to exist since 1974, the structures and functions of methyltransferases responsible for writing m<sup>6</sup> 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<sup>6</sup> position of adenosine, producing m<sup>6</sup> 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<sup>6</sup> 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<sup>6</sup> 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<sup>6</sup> A marks in human viruses and parasites, assigning m<sup>6</sup> A marks in the transcriptome to specific methyltransferases, small molecules targeting m<sup>6</sup> A methyltransferases, and the enzymes responsible for hypermodified m<sup>6</sup> A marks and their biological functions in humans. Understanding m<sup>6</sup> A methyltransferases is a critical steppingstone toward establishing the m<sup>6</sup> A epitranscriptome and more broadly the RNome. 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引用次数: 0
摘要
尽管近 75 年前就发现了修饰核酸,但它们的生物学功能仍在不断被阐明。N6 -甲基腺苷(m6 A)是真核生物信使 RNA(mRNA)中最丰富的修饰,在非编码 RNA(包括长非编码 RNA、核糖体 RNA 和小核 RNA)中也被检测到。一般来说,m6 A 标记会改变 RNA 的二级结构,并引发独特的 RNA 蛋白相互作用,从而改变剪接、mRNA 更替和翻译等。虽然早在 1974 年就知道人类 RNA 中存在 m6 A 标记,但负责书写 m6 A 标记的甲基转移酶的结构和功能直到最近才被确定。迄今为止,已证实有四种人类甲基转移酶能催化甲基基团从 S-腺苷蛋氨酸(SAM)转移到腺苷的 N6 位,从而产生 m6 A:甲基转移酶样蛋白(METTL)3/METTL14 复合物、METTL16、METTL5 和含锌指 CCHC 域蛋白 4。尽管这些甲基转移酶具有独特的 RNA 靶标,但所有人类 m6 A RNA 甲基转移酶都包含一个 Rossmann 折叠结构,其中有一个保守的 SAM 结合口袋,这表明它们利用类似的催化机制进行甲基转移。对于每一种人类 m6 A RNA 甲基转移酶,我们都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 m6 A 标记、将转录组中的 m6 A 标记分配给特定的甲基转移酶、以 m6 A 甲基转移酶为靶标的小分子、负责超修饰 m6 A 标记的酶及其在人类中的生物学功能。了解 m6 A 甲基转移酶是建立 m6 A 表转录组和更广泛的 RN 组的关键一步。本文归类于RNA 与蛋白质及其他分子的相互作用 > 蛋白质与 RNA 的识别 RNA 与蛋白质及其他分子的相互作用 > RNA 蛋白复合物 RNA 与蛋白质及其他分子的相互作用 > 蛋白质与 RNA 的相互作用:功能影响。
Ghost authors revealed: The structure and function of human N6 -methyladenosine RNA methyltransferases.
Despite the discovery of modified nucleic acids nearly 75 years ago, their biological functions are still being elucidated. N6 -methyladenosine (m6 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, m6 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 m6 A marks in human RNAs have been known to exist since 1974, the structures and functions of methyltransferases responsible for writing m6 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 N6 position of adenosine, producing m6 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 m6 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 m6 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 m6 A marks in human viruses and parasites, assigning m6 A marks in the transcriptome to specific methyltransferases, small molecules targeting m6 A methyltransferases, and the enzymes responsible for hypermodified m6 A marks and their biological functions in humans. Understanding m6 A methyltransferases is a critical steppingstone toward establishing the m6 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.
期刊介绍:
WIREs RNA aims to provide comprehensive, up-to-date, and coherent coverage of this interesting and growing field, providing a framework for both RNA experts and interdisciplinary researchers to not only gain perspective in areas of RNA biology, but to generate new insights and applications as well. Major topics to be covered are: RNA Structure and Dynamics; RNA Evolution and Genomics; RNA-Based Catalysis; RNA Interactions with Proteins and Other Molecules; Translation; RNA Processing; RNA Export/Localization; RNA Turnover and Surveillance; Regulatory RNAs/RNAi/Riboswitches; RNA in Disease and Development; and RNA Methods.