2. Academic Validation
  3. A cohort of mRNAs undergo high-stoichiometry NSUN6-mediated site-specific m5C modification

A cohort of mRNAs undergo high-stoichiometry NSUN6-mediated site-specific m5C modification

  • Nat Commun. 2025 Jul 4;16(1):6119. doi: 10.1038/s41467-025-60873-4.
Yuan-Yuan Zhang # 1,  Cai-Tao Li # 1 2,  You-Jia Zhou 1,  Hao Li 1,  Jing Li 1,  Qing-Ping Xiong 2,  Wei Zhou 1,  Wenze Huang 3,  Qiangfeng Cliff Zhang 3,  Yangfei Xiang 1,  En-Duo Wang 4 5,  Beisi Xu 6,  Ru-Juan Liu 7
Affiliations

Affiliations

  • 1 School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • 2 State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, China.
  • 3 MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China.
  • 4 School of Life Science and Technology, ShanghaiTech University, Shanghai, China. edwang@sibcb.ac.cn.
  • 5 State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, China. edwang@sibcb.ac.cn.
  • 6 Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, USA. Beisi.Xu@STJUDE.ORG.
  • 7 School of Life Science and Technology, ShanghaiTech University, Shanghai, China. liurj@shanghaitech.edu.cn.
  • # Contributed equally.
PMID: 40615396 DOI: 10.1038/s41467-025-60873-4
Abstract

mRNA modifications are vital in regulating cellular processes. Beyond N6-methyladenosine (m6A), most Other internal mRNA modifications lack dedicated catalytic machinery and are typically introduced by tRNA-modifying Enzymes. The distribution and stoichiometry of these modifications on mRNAs remain debated and require further validation. Furthermore, their precise function remains controversial due to the challenges of excluding the intricate combinational effects of tRNA modifications. Here, we biochemically validate that NSUN6, a tRNA structure-dependent methyltransferase, independently catalyzes 5-methylcytidine (m5C) formation with robust activity on mRNA by recognizing the CUCCA motif in a certain stem-loop structure. NSUN6 employs different strategies to recognize tRNA and mRNA substrates. By introducing mutations, we further separate its catalytic capabilities toward mRNA and tRNA revealing that NSUN6 promotes breast Cancer cell migration depending on mRNA m5C modification. Mechanistically, a cohort of mRNAs involved in cell migration carries high levels of NSUN6-mediated site-specific m5C modification, thus being stabilized by the preferential binding of m5C readers YBX1 and YBX3. Moreover, introducing a single-site high-level m5C can significantly increase the stability of therapeutic mRNAs in cells. Our findings underscore the pivotal role of m5C-modified mRNAs in promoting breast Cancer cell migration and their potential for therapeutic applications.

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