Structural Insights Into m6A-Erasers: A Step Toward Understanding Molecule Specificity and Potential Antiviral Targeting.
Structural Insights Into m6A-Erasers: A Step Toward Understanding Molecule Specificity and Potential Antiviral Targeting.
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DOI：
10.3389/fcell.2020.587108
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发表时间：
2020
影响因子：
5.5
通讯作者：
Munir M
中科院分区：
文献类型：
--
作者：
Bayoumi M;Munir M
细胞RNA可以在细胞周期中获得各种化学修饰，并且令人信服的证据强调了这些修饰在决定RNA代谢以及随后的细胞生理学中的重要性。在众多修饰中，腺苷n6位（m6A）的甲基化是信使RNA中最重要和最丰富的内部修饰。在大多数真核生物中，m6A标记由甲基转移酶复合物蛋白（写入者）安装，并被去甲基化酶如FTO和ALKBH5（擦除者）动态逆转。RNA转录本上合并的m6A标记被称为读取器的m6A结合蛋白识别。最近的表观遗传学研究明确强调了m6A去甲基化酶与一系列生物医学方面的关联，包括人类疾病、癌症和代谢紊乱。此外，m6A擦除子的去甲基化机制是未来RNA生物学基础研究的一个新领域。在这篇综述中，我们重点介绍了m6A擦除剂的各种生理、病理和病毒调节作用的最新进展。此外，我们的目标是分析众所周知的m6a -去甲基化酶的结构见解，以评估其底物结合的特异性、效率和选择性。对细胞和病毒RNA代谢的了解将有助于揭示去甲基化酶对m6a的特异性识别，并将为未来开发有效的治疗各种癌症的药物提供基础，并为开发抗病毒药物开辟新的途径。
The cellular RNA can acquire a variety of chemical modifications during the cell cycle, and compelling pieces of evidence highlight the importance of these modifications in determining the metabolism of RNA and, subsequently, cell physiology. Among myriads of modifications, methylation at the N6-position of adenosine (m6A) is the most important and abundant internal modification in the messenger RNA. The m6A marks are installed by methyltransferase complex proteins (writers) in the majority of eukaryotes and dynamically reversed by demethylases such as FTO and ALKBH5 (erasers). The incorporated m6A marks on the RNA transcripts are recognized by m6A-binding proteins collectively called readers. Recent epigenetic studies have unequivocally highlighted the association of m6A demethylases with a range of biomedical aspects, including human diseases, cancers, and metabolic disorders. Moreover, the mechanisms of demethylation by m6A erasers represent a new frontier in the future basic research on RNA biology. In this review, we focused on recent advances describing various physiological, pathological, and viral regulatory roles of m6A erasers. Additionally, we aim to analyze structural insights into well-known m6A-demethylases in assessing their substrate binding-specificity, efficiency, and selectivity. Knowledge on cellular and viral RNA metabolism will shed light on m6A-specific recognition by demethylases and will provide foundations for the future development of efficacious therapeutic agents to various cancerous conditions and open new avenues for the development of antivirals.