Miller Lucas G, Demny Madeline, Tamamis Phanourios, Contreras Lydia M
McKetta Department of Chemical Engineering, The University of Texas at Austin, Austin, TX, USA.
Artie McFerrin Department of Chemical Engineering, Texas A&M University, College Station, TX, USA.
Comput Struct Biotechnol J. 2023 Jun 30;21:3541-3556. doi: 10.1016/j.csbj.2023.06.018. eCollection 2023.
To date, over 150 chemical modifications to the four canonical RNA bases have been discovered, known collectively as the epitranscriptome. Many of these modifications have been implicated in a variety of cellular processes and disease states. Additional work has been done to identify proteins known as "readers" that selectively interact with RNAs that contain specific chemical modifications. Protein interactomes with N6-methyladenosine (mA), N1-methyladenosine (mA), N5-methylcytosine (mC), and 8-oxo-7,8-dihydroguanosine (8-oxoG) have been determined, mainly through experimental advances in proteomics techniques. However, relatively few proteins have been confirmed to bind directly to RNA containing these modifications. Furthermore, for many of these protein readers, the exact binding mechanisms as well as the exclusivity for recognition of modified RNA species remain elusive, leading to questions regarding their roles within different cellular processes. In the case of the YT-521B homology (YTH) family of proteins, both experimental and techniques have been leveraged to provide valuable biophysical insights into the mechanisms of mA recognition at atomic resolution. To date, the YTH family is one of the best characterized classes of readers. Here, we review current knowledge about epitranscriptome recognition of the YTH domain proteins from previously published experimental and computational studies. We additionally outline knowledge gaps for proteins beyond the well-studied human YTH domains and the current techniques and resources that can enable investigation of protein interactions with modified RNA outside of the YTH-mA context.
迄今为止，已发现对四种标准RNA碱基进行的150多种化学修饰，它们统称为表观转录组。其中许多修饰与多种细胞过程和疾病状态有关。人们还开展了更多工作来鉴定一类被称为“读取器”的蛋白质，这类蛋白质能与含有特定化学修饰的RNA选择性地相互作用。主要通过蛋白质组学技术的实验进展，已经确定了与N6-甲基腺苷（m6A）、N1-甲基腺苷（m1A）、N5-甲基胞嘧啶（m5C）和8-氧代-7,8-二氢鸟苷（8-oxoG）相互作用的蛋白质组。然而，相对较少的蛋白质已被证实能直接结合含有这些修饰的RNA。此外，对于许多这类蛋白质读取器而言，确切的结合机制以及对修饰RNA种类识别的特异性仍然难以捉摸，这引发了关于它们在不同细胞过程中作用的疑问。就YT-521B同源（YTH）蛋白家族而言，实验和计算技术都已被用于在原子分辨率下为m6A识别机制提供有价值的生物物理见解。迄今为止，YTH家族是特征最明确的读取器类别之一。在这里，我们回顾了先前发表的实验和计算研究中关于YTH结构域蛋白对表观转录组识别的现有知识。我们还概述了除了研究充分的人类YTH结构域之外的蛋白质的知识空白，以及当前能够在YTH-m6A背景之外研究蛋白质与修饰RNA相互作用的技术和资源。
