Sequence-and structure-selective mRNA m5C methylation by NSUN6 in animals

• 作者: Jianheng Liu Tao Huang Yusen Zhang Tianxuan Zhao Xueni Zhao Wanying Chen Rui Zhang
• 来源期刊: 国家科学评论（英文版）
• 年，卷（期）: 2021,（6）
• 所属期刊栏目: RESEARCH ARTICLES
• 页码范围: 130-141
• 页数: 12页
• 语种: 英文
• DOI: 10.1093/nsr/nwaa273

摘要

mRNA m5C,which has recently been implicated in the regulation ofmRNA mobility,metabolism and translation,plays important regulatory roles in various biological events.Two types ofm5C sites are found in mRNAs.Type Ⅰ m5C sites,which contain a downstream G-rich triplet motif and are computationally predicted to be located at the 5'end of putative hairpin structures,are methylated by NSUN2.Type Ⅱ m5C sites contain a downstream UCCA motif and are computationally predicted to be located in the loops of putative hairpin structures.However,their biogenesis remains unknown.Here we identified NSUN6,a methyltransferase that is known to methylate C72 of tRNAThr and tRNACys,as an mRNA methyltransferase that targets Type Ⅱ m5C sites.Combining the RNA secondary structure prediction,miCLIP,and results from a high-throughput mutagenesis analysis,we determined the RNA sequence and structural features governing the specificity ofNSUN6-mediated mRNA methylation.Integrating these features into an NSUN6-RNA structural model,we identified an NSUN6 variant that largely loses tRNA methylation but retains mRNA methylation ability.Finally,we revealed a weak negative correlation between m5 C methylation and translation efficiency.Our findings uncover that mRNA m5C is tightly controlled by an elaborate two-enzyme system,and the protein-RNA structure analysis strategy established may be applied to other RNA modification writers to distinguish the functions of different RNA substrates of a writer protein.