人RNA m5C甲基转移酶NSUN2的底物选择性，这一成果由德克萨斯大学Yunsun Nam团队经过不懈努力而取得。2026年5月27日出版的《自然》发表了这项成果。
在这里，该研究团队展示了NSUN2如何在其催化循环的不同阶段与RNA底物相互作用以修饰胞苷。
此外，小组展示了RNA结构在促进NSUN2在多个tRNA位置的活性中的作用。该课题组研究人员鉴定出m5C修饰位点周围的RNA双链是甲基化的关键识别元件，这使他们能够获得最小化的底物，该底物捕获了NSUN2底物的首选特征-在第一个茎的5端包含CNNRR基序的双茎结构。深入了解底物特异性NSUN2酶活性的机制为理解和治疗NSUN2依赖性甲基化提供了机会。总的来说，他们的工作强调了RNA结构和序列在定义底物特异性和调节RNA修饰酶中的作用。
研究人员表示，RNA修饰的特异性沉积对于调节基因表达非常重要。5-甲基胞嘧啶（m5C）是一种常见的表转录组修饰，而NSUN2是负责各种类型RNA的m5C甲基化的关键酶。NSUN2的失调与许多疾病有关，包括癌症和神经系统疾病。NSUN2的多功能性使他们对其底物特异性和在生物学和疾病中的分子作用的理解复杂化。
附：英文原文
Title: Substrate selectivity of the human RNA m5C methyltransferase NSUN2
Author: Canepa, Jacob, Ruiz-Arroyo, Victor M., Schlamowitz, Netanya S., Nam, Yunsun
Issue&Volume: 2026-05-27
Abstract: Specific deposition of RNA modifications is important for regulating gene expression1,2. 5-Methylcytosine (m5C) is a common epitranscriptomic modification, and NSUN2 is a key enzyme responsible for m5C methylation of various types of RNA. Dysregulation of NSUN2 is associated with numerous diseases, including cancers and neurological disorders3. The versatility of NSUN2 complicates our understanding of its substrate specificity and molecular roles in biology and disease. Here we show how NSUN2 interacts with RNA substrates at distinct stages of its catalytic cycle to modify cytidines. Furthermore, we show the role of RNA structure in facilitating NSUN2 activity at multiple tRNA positions. We identify RNA duplexes surrounding the m5C modification site as crucial recognition elements for methylation, which enabled us to derive a minimized substrate that captures the preferred features of an NSUN2 substrate—a dual-stem structure containing the CNNRR motif at the 5′ end of the first stem. Insights into the mechanisms underlying substrate-specific NSUN2 enzymatic activity provide opportunities for understanding and therapeutically targeting NSUN2-dependent methylation. Overall, our work highlights the roles of RNA structure and sequence in defining substrate specificity and regulating RNA-modifying enzymes.
DOI: 10.1038/s41586-026-10582-9