5-甲基尿苷(m5U)RNA修饰的生物学功能研究进展★

doi:10.6023/A25050152

化学学报 ›› 2025, Vol. 83 ›› Issue (9): 1046-1054.DOI: 10.6023/A25050152 上一篇下一篇

研究展望

5-甲基尿苷(m⁵U)RNA修饰的生物学功能研究进展^★

武传硕^a, 程靓^a^,^b^,^*()

^a 中国科学院化学研究所北京分子科学国家研究中心中国科学院分子识别与功能实验室分子科学科教融合卓越创新中心北京 100190
^b 中国科学院大学北京 100049

投稿日期:2025-05-10 发布日期:2025-07-04

作者简介:

武传硕博士, 1995年出生于山东省聊城市. 2015年于青岛科技大学获得化学学士学位; 2019年于湘潭大学获得有机化学硕士学位; 2024年于中国科学院化学研究所获得化学生物学博士学位. 2024年入选北京分子科学国家研究中心BMS Fellow, 主要研究方向为: 组蛋白修饰的化学调控及RNA修饰的测序研究.

程靓研究员, 2004年本科毕业于北京师范大学, 2009年博士研究生毕业于中国科学院化学研究所, 获理学博士学位; 2011年起在美国哥伦比亚大学化学系从事博士后研究; 2015年入选中国科学院化学研究所“引进国外杰出青年人才计划”, 任研究员, 博士生导师. 先后在PNAS、Angew. Chem. Int. Ed.、CCS Chem.、Adv. Sci.上发表论文70余篇. 入选首批中国科协/中国化学会青年人才托举工程, 中国科学院北京分院“启明星”计划, Thieme Chemistry Journals Award、中国科学院朱李月华优秀教师奖和国家自然科学基金委“优秀青年基金”资助.

^★ “中国青年化学家”专辑.

基金资助:
国家重点研发计划(2025YFA0920900); 中国科学院战略性先导科技专项(XDB0960103); 北京分子科学国家研究中心(BNLMS-CXTD-202401)

Recent Advances in the Biological Functions of 5-Methyluridine (m⁵U) RNA Modification^★

Chuanshuo Wu^a, Liang Cheng^a^,^b^,^*()

^a Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
^b University of Chinese Academy of Sciences, Beijing 100049, China

Received:2025-05-10 Published:2025-07-04
Contact: * E-mail: chengl@iccas.ac.cn; Tel.: 010-61943102
About author:
^★ For the VSI “Rising Stars in Chemistry”.
Supported by:
National Key R&D Program of China(2025YFA0920900); Strategic Priority Research Program of the Chinese Academy of Sciences(XDB0960103); Beijing National Laboratory for Molecular Sciences(BNLMS-CXTD-202401)

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摘要/Abstract

RNA修饰在调控基因表达和维持细胞稳态中发挥着关键作用. 尽管N⁶-甲基腺苷(m⁶A)和5-甲基胞苷(m⁵C)等RNA修饰已被广泛研究, 但5-甲基尿苷(m⁵U)作为一种高度保守且分布广泛的RNA修饰, 其研究仍相对滞后. 近年来, 通过质谱及代谢掺入测序的方法, 在哺乳动物细胞mRNA上也发现了m⁵U的存在. tRNA上的m⁵U修饰也被证明在促进tRNA折叠、提升tRNA稳定性、调控tRNA修饰景观、核糖体易位以及细胞适应性方面发挥着关键作用. 本文系统总结了m⁵U的研究进展, 重点介绍其在mRNA上的发现、不同物种间形成机制的差异、tRNA上m⁵U生物学功能研究及其相关酶的作用, 并结合已有研究成果探讨其潜在的疾病关联, 并对未来的发展方向提出展望.

关键词: RNA修饰, 5-甲基尿苷, 甲基转移酶, 细胞适应性, RNA稳定性

RNA modifications play a pivotal role in regulating gene expression and maintaining cellular homeostasis. While modifications such as N⁶-methyladenosine (m⁶A) and 5-methylcytosine (m⁵C) have been extensively studied, 5-methyluridine (m⁵U) remains relatively understudied despite its abundance and evolutionary conservation, particularly in tRNA. In recent years, despite its low abundance, m⁵U has also been found on mRNA in mammalian cells through high resolution mass spectrometry and metabolic incorporation sequencing method. However, due to the lack of high-throughput sequencing methods, the distribution and biological functions of m⁵U modification on mRNA are still remaining unknown. Various species employ diverse enzymes and traverse two distinct pathways to form m⁵U on tRNA, underscoring the significance and diversity of m⁵U modification throughout evolutionary history. The m⁵U modification on tRNA has also been shown to play a key role in promoting tRNA folding, enhancing tRNA stability, regulating tRNA modification landscape, ribosome translocation, and cellular fitness. The human tRNA methyltransferase TRMT2A, beyond its catalytic role, influences translation fidelity and cell cycle, with implications in cancer and neurodegeneration. Despite some advancements in the study of m⁵U, several challenges persist. For instance, the dynamic regulation mechanism underlying m⁵U modification remains unclear. The precise role of m⁵U in the onset and progression of diseases is still not fully understood, and its potential worth in clinical diagnosis and treatment awaits further exploration. Integrating cutting-edge technologies and multi-omics approaches will be essential to unravel m⁵U's full biological and biomedical potential, offering new insights into RNA epigenetics and disease mechanisms. This perspective highlights recent progress in the study of m⁵U, including its discovery on mRNA, catalytic enzymes, cross-talk with other modifications, and regulatory functions. We also discuss the emerging links between m⁵U and human diseases, and outline the current challenges and future directions in decoding the dynamic regulation and biomedical significance of this RNA modification.

Key words: RNA modification, 5-methyluridine (m⁵U), tRNA methyltransferase 2 homolog A, cell fitness, RNA stability

引用此文

武传硕, 程靓. 5-甲基尿苷(m⁵U)RNA修饰的生物学功能研究进展^★[J]. 化学学报, 2025, 83(9): 1046-1054.

Chuanshuo Wu, Liang Cheng. Recent Advances in the Biological Functions of 5-Methyluridine (m⁵U) RNA Modification^★[J]. Acta Chimica Sinica, 2025, 83(9): 1046-1054.

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图/表 6

图1. 高度保守的m5U54修饰. (A) m5U54位于tRNA TΨC茎环区域; (B) m5U54几乎存在于所有物种中

Figure 1. Conserved 5-methyluridine (m5U54) tRNA modification. (A) m5U54 is located in tRNA TΨC stem or loop region; (B) m5U54 is present in almost all species

图2. 不同物种中m5U的形成机制. (A)以SAM为甲基供体的酶催化机制(哺乳动物细胞、大肠杆菌等); (B)以N5,N10-亚甲基四氢叶酸为甲基供体的酶催化机制(部分革兰氏阳性菌如: 枯草芽孢杆菌及支原体等)

Figure 2. Mechanism of m5U formation in different species. (A) Enzyme catalytic mechanism using SAM as a methyl donor (mammalian cells, E. coli); (B) Enzyme catalytic mechanism using N5,N10-methylenetetrahydrofolate as a methyl donor (Some gram positive bacteria, such as B. subtilis and mycoplasma)

图3. Ψ55、m5U54及m1A58之间的互作. (A)Ψ55、m5U54及m1A58引入的先后顺序; (B)Trm6/Trm61催化含有Ψ55、m5U54的tRNA A58甲基化的速率差别. 图3来自参考文献[21]

Figure 3. Figure 3 Cross-talk between Ψ55, m5U54 and m1A58. (A) The introduce order of Ψ55, m5U54 and m1A58 in tRNA. (B) The methylation rate of tRNA A58 containing Ψ55 or m5U54 catalyzed by Trm6/Trm61. was adapted from ref. [21]. Available under a CC-BY license. Copyright 2023, The Authors

图4. tRNA m5U54与其它修饰的互作. (A)敲除trmA、truB后大肠杆菌tRNA acp3U47变化的热图; (B) S4U8的变化; (C)敲除trmA后大肠杆菌tRNA上的修饰变化(通过LC-MS/MS定量). 图4A、 4B来自参考文献[24], 图4C来自参考文献[25]

Figure 4. Cross-talk between m5U54 and other modifications in tRNA. (A) Heatmap depicting the variations in Escherichia coli tRNA acp3U47 following the knockout of trmA and truB; (B) changes of S4U8; (C) Modification changes of E. coli tRNA afterΔtrmA. Figures 4A, 4B were adapted from ref. [24]. Available under a CC-BY-NC-ND 4.0 license. Copyright 2024, The Authors; Figure 4C was adapted from ref. [25]. Available under a CC-BY-NC-ND 4.0 license. Copyright 2024, The Authors

图5. (A)温度依赖的m5s2U54修饰; (B) trmA/truB的生物学功能. 图5B来自参考文献[24]

Figure 5. (A) Temperature-dependent modification of m5s2U54; (B) Biological function of trmA and truB. Figure 5B was adapted from ref. [24]. Available under a CC-BY-NC-ND 4.0 license. Copyright 2024, The Authors

图6. (A) TrmA和tRNA的T臂结合的结构(PDB ID: 3BT7); (B) TrmA RNA结合结构域中F106-H125残基与tRNA D臂和T臂相互作用的结构示意图; (C) TRMT2A对翻译保真度的影响. 图6A、6B来自参考文献[31], 图6C来自参考文献[32]

Figure 6. (A) Structure of TrmA bound to T arm of tRNA (PDB ID: 3BT7); (B) Structural model for the disruption of D arm and T arm tertiary interactions in tRNA by the F106-H125 wedge in the RNA-binding domain of TrmA; (C) TRMT2A’s impact on translation fidelity. Figure 6A, 6B were adapted from ref. [31]. Available under a CC-BY-NC license. Copyright 2020, The Authors; Figure 6C was adapted from ref. [32]. Available under a CC-BY license. Copyright 2023, The Authors

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5-甲基尿苷(m⁵U)RNA修饰的生物学功能研究进展^★

Recent Advances in the Biological Functions of 5-Methyluridine (m⁵U) RNA Modification^★

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