哺乳动物RNA 5-甲基胞嘧啶修饰相关蛋白的结构与功能研究

Nucleic acids are composed of nucleotides, they encode and store the genetic information of life. Recent advances in identifying more and more chemical modifications of nucleic acids were benefited tremendously from rapid development of high-throughput sequencing technology and analytical chemistry. More than 160 known ribonucleoside modifications have been found in RNA. RNA methylation is the most abundant modifications in RNA, which is involved in gene expression, nucleic acids metabolism and cell signaling. Many diseases are due to the dysregulation of RNA methylation. We will focus on the dynamic regulation of mammalian RNA 5-methylcytosine (m5C) in our research to investigate the molecular mechanism of RNA m5C reader and methyltransferase by using the structural biology based multiple methods. This research is critical for us to explore their biological functions, which also provides the molecular basis of new targets for therapy against related diseases.

核酸是由核苷酸聚合而成的生物大分子，编码了生命的基本遗传信息。随着高通量测序技术和检测技术的发展，人们发现在核苷酸上还存在着许多不同种类的化学修饰，仅在RNA中就发现超过160多种的化学修饰方式。RNA甲基化是RNA化学修饰中丰度最高的一种修饰方式，该修饰广泛地参与了基因表达、核酸代谢及细胞信号通路等众多生理功能，甲基化水平调控的异常往往会导致重大疾病的发生。本项目中我们将关注哺乳动物RNA 5-甲基胞嘧啶修饰（m5C）相关的重要蛋白质分子机器，综合运用以结构生物学为主的多种研究手段阐明RNA m5C修饰的识别蛋白和甲基转移酶发挥功能的分子机制，以助于我们找到探索其生物学功能的突破口，并为相关疾病的治疗提供理论基础。

生物大分子修饰调控着生命活动的基本功能，发现和鉴定这些化学修饰在生物体内识别的动态调控机制，将有助于我们找到其生物学功能的突破口，并为探讨因该修饰的异常导致的相关疾病提供重要的理论基础。其中甲基化修饰是丰度最高也是最为常见的一种化学修饰，在本项目中，我们针对甲基化修饰的识别器蛋白开展了结构和功能的探索，从分子层面上解析了这些蛋白质的识别机制和生理功能，我们揭示了RNA两种甲基化修饰m5C和m6A的分子识别机制，探索了这些修饰在核酸代谢、干细胞发育以及3’末端加工等重要生命过程中的生物学功能，此外还解析了AUB蛋白甲基化修饰在piRNA产生过程中的重要生物学功能。截止到2022年12月项目执行完毕，共发表4篇标注论文。