Volume: 16, Issue: 2

Review

Structural Insights into N6-methyladenosine (m6A) Modification in the Transcriptome

Jinbo Huang, Ping Yin

More than 100 types of chemical modifications in RNA have been well documented. Recently, several modifications, such as N6-methyladenosine (m6A), have been detected in mRNA, opening the window into the realm of epitranscriptomics. The m6A modification is the most abundant modification in mRNA and non-coding RNA (ncRNA). At the molecular level, m6A affects almost all aspects of mRNA metabolism, including splicing, translation, and stability, as well as microRNA (miRNA) maturation, playing essential roles in a range of cellular processes. The m6A modification is regulated by three classes of proteins generally referred to as the “writer” (adenosine methyltransferase), “eraser” (m6A demethylating enzyme), and “reader” (m6A-binding protein). The m6A modification is reversibly installed and removed by writers and erasers, respectively. Readers, which are members of the YT521-B homology (YTH) family proteins, selectively bind to RNA and affect its fate in an m6A-dependent manner. In this review, we summarize the structures of the functional proteins that modulate the m6A modification, and provide our insights into the m6A-mediated gene regulation.
目前在RNA中已经发现有超过100种的化学修饰。最近在真核mRNA上发现一类新修饰,即腺嘌呤甲基化(m6A),拓宽了对表观转录组学(epitranscriptomics)的认识。m6A修饰是在mRNA和非编码RNA(ncRNA)中最丰富的一种修饰。m6A影响mRNA的代谢,包括剪接、翻译和稳定性,以及microRNA的成熟。这些被m6A调节的RNA代谢过程在这一系列的细胞进程中扮演着重要角色。在体内,m6A修饰主要被三类蛋白分子调节,包括催化在RNA甲基化的甲基转移酶,一般被称为“编码器”(writer,m6A甲基转移酶);去除在RNA上甲基化的去甲基化酶,被称为“消码器”(eraser,m6A去甲基化酶);识别RNA上甲基化的蛋白,被称为“读码器”(reader,m6A结合蛋白)。因此,m6A甲基化修饰是个可逆的过程,分别由编码器写入和消码器消除,并且还可以通过读码器识别,参与并影响到一系列的生物学过程。在这篇综述中,我们从结构生物学的角度,系统地总结了这些蛋白或者复合物的结构特征,对调节m6A修饰的分子机理进行了阐述和讨论,为m6A介导的基因表达调控提供了一些见解。

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Review

YTH Domain: A Family of N6-methyladenosine (m6A) Readers

Shanhui Liao, Hongbin Sun, Chao Xu

Like protein and DNA, different types of RNA molecules undergo various modifications. Accumulating evidence suggests that these RNA modifications serve as sophisticated codes to mediate RNA behaviors and many important biological functions. N6-methyladenosine (m6A) is the most abundant internal RNA modification found in a variety of eukaryotic RNAs, including but not limited to mRNAs, tRNAs, rRNAs, and long non-coding RNAs (lncRNAs). In mammalian cells, m6A can be incorporated by a methyltransferase complex and removed by demethylases, which ensures that the m6A modification is reversible and dynamic. Moreover, m6A is recognized by the YT521-B homology (YTH) domain-containing proteins, which subsequently direct different complexes to regulate RNA signaling pathways, such as RNA metabolism, RNA splicing, RNA folding, and protein translation. Herein, we summarize the recent progresses made in understanding the molecular mechanisms underlying the m6A recognition by YTH domain-containing proteins, which would shed new light on m6A-specific recognition and provide clues to the future identification of reader proteins of many other RNA modifications.
像蛋白和DNA一样,不同的RNA分子也会进行不同的修饰。大量证据表明这些RNA修饰是一种复杂代码,用来调控RNA的行为和很多重要的生物学功能。m6A是真核生物RNA中存在的一种最为丰富的内部RNA修饰,m6A修饰在信使RNA,转运RNA,核糖体RNA和长链非编码 RNA等RNA中广泛存在。在哺乳动物细胞中,m6A可通过甲基转移酶复合体形成并被去甲基化酶去除,从而保证了这种修饰是动态可逆的。此外,m6A可被含有YT521-B同源(YTH)结构域的蛋白识别,进而指导不同的复合物调节RNA信号传导途径,如:RNA代谢,RNA剪接,RNA折叠和蛋白质翻译。因此,我们总结了近期在研究含有YTH结构域蛋白识别m6A的分子机制方面的进展,这将会为研究m6A特异性识别带来新的亮点,并为将来确定识别其他RNA修饰的蛋白提供了线索。

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