以色列魏茨曼科学研究所Schraga Schwartz研究小组近日取得一项新成果。经过不懈努力，他们首次证实天然 RNA 磷酸骨架修饰及其对应的酶促修饰体系。相关论文于近日发表在《细胞》杂志上。
目前已有超过 150 种修饰拓展了 RNA 的碱基编码体系，但所有已知天然修饰均发生在核碱基或核糖上，尚未发现磷酸骨架上存在天然修饰。与之不同，硫代磷酸（PS）是将磷酸基团的一个非桥连氧原子替换为硫原子，这类结构是 RNA 药物的核心，却始终未能在天然 RNA 中得到可靠检出。本研究建立了基于测序与质谱的技术方法，可在单核苷酸分辨率下对 RNA 硫代磷酸修饰进行定量定位。在多种古菌中，我们在核糖体 RNA（rRNA）与转运 RNA（tRNA）的热点区域发现具有立体特异性的硫代磷酸修饰；该修饰受硫元素供给与温度动态调控。研究还鉴定出一类多样化的酶家族，可选择性修饰 tRNA/rRNA 底物，这类酶在演化上的有无分布与硫代磷酸修饰的物种分布相吻合。敲除该类酶会造成菌株致死或温度敏感；功能实验证实 tRNA 上的硫代磷酸修饰能够提升 tRNA 稳定性。本研究首次证实天然 RNA 磷酸骨架修饰及其对应的酶促修饰体系，为后续机制与功能研究奠定基础。
附：英文原文
Title: Phosphate backbone epitranscriptomics: Discovery of natural RNA phosphorothioates and their writer machinery
Author: Alexander Maman, Yuko Nobe, Kristin A. Fluke, Katrin Weidenbach, Alexandra N. Harte, Brett W. Burkhart, Jakub Nowak, Priyadarshini Mukherjee, Deepak Kumar Choudhary, Anatoly Kustanovich, Ronit Nir, Katharina Vogl, Kiall Suazo, Danijela Radovanovi, Donna Matzov, Walter Rossmanith, Jordan L. Meier, Moran Shalev-Benami, Dina Grohmann, Kylie D. Allen, Eric Westhof, Sebastian Glatt, Ruth A. Schmitz, Thomas J. Santangelo, Masato Taoka, Schraga Schwartz
Abstract: Over 150 modifications expand the RNA alphabet, yet all known natural modifications occur on nucleobases or ribose sugars, with none identified on the phosphate backbone. In contrast, phosphorothioates (PSs), in which a non-bridging phosphate oxygen is replaced with sulfur, are central to RNA therapeutics but have never been reliably detected in natural RNAs. Here, we develop sequencing- and mass spectrometry-based approaches to quantitatively map RNA PSs at single-nucleotide resolution. Across diverse archaeal species, we identify stereospecific PS modifications at rRNA and tRNA hotspots, which are dynamically regulated by sulfur availability and temperature. We uncover a diverse enzyme family that selectively modifies tRNA/rRNA substrates and whose evolutionary presence/absence matches the distribution of PSs. Enzyme loss causes inviability or temperature sensitivity, and functional analyses reveal that tRNA PSs enhance tRNA stability. These findings establish the first natural RNA phosphate-backbone modification and its enzymatic machinery, providing a foundation for mechanistic and functional exploration.
DOI: 10.1016/j.cell.2026.08.034
Source: https://www.cell.com/cell/abstract/S0092-8674(26)01007-X