Linder Bastian, Sharma Puneet, Wu Jie, Birbaumer Tosca, Eggers Cristian, Murakami Shino, Ott Roman E, Fenzl Kai, Vorgerd Hannah, Erhard Florian, Jaffrey Samie R, Leidel Sebastian A, Steinmetz Lars M
Genome Biology Unit, European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany.
Max-Planck-Research Group for RNA Biology, Max Planck Institute for Molecular Biomedicine, 48149 Münster, Germany; Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, 3012 Bern, Switzerland.
Cell. 2025 Jul 10;188(14):3715-3727.e13. doi: 10.1016/j.cell.2025.04.013. Epub 2025 Apr 30.
Chemically modified nucleotides in mRNA are critical regulators of gene expression, primarily through interactions with reader proteins that bind to these modifications. Here, we present a mechanism by which the epitranscriptomic mark N-methyladenosine (mA) is read by tRNAs during translation. Codons that are modified with mA are decoded inefficiently by the ribosome, rendering them "non-optimal" and inducing ribosome collisions on cellular transcripts. This couples mRNA translation to decay. 5-Methoxycarbonylmethyl-2-thiouridine (mcmsU) in the tRNA anticodon loop counteracts this effect. This unanticipated link between the mRNA and tRNA epitranscriptomes enables the coordinated decay of mRNA regulons, including those encoding oncogenic signaling pathways. In cancer, dysregulation of the mA and mcmsU biogenesis pathways-marked by a shift toward more mcmsU-is associated with more aggressive tumors and poor prognosis. Overall, this pan-epitranscriptomic interaction represents a novel mechanism of post-transcriptional gene regulation with implications for human health.
mRNA中的化学修饰核苷酸是基因表达的关键调节因子，主要通过与结合这些修饰的读取蛋白相互作用来实现。在此，我们提出了一种机制，即翻译过程中tRNA读取表观转录组标记N-甲基腺苷（mA）。被mA修饰的密码子被核糖体解码的效率低下，使其成为“非最优”密码子，并在细胞转录本上引发核糖体碰撞。这将mRNA翻译与降解联系起来。tRNA反密码子环中的5-甲氧基羰基甲基-2-硫代尿苷（mcmsU）可抵消这种效应。mRNA和tRNA表观转录组之间这种意想不到的联系使得mRNA调控子能够协调降解，包括那些编码致癌信号通路的调控子。在癌症中，mA和mcmsU生物合成途径的失调（以向更多mcmsU转变为特征）与更具侵袭性的肿瘤和不良预后相关。总体而言，这种全表观转录组相互作用代表了一种新的转录后基因调控机制，对人类健康具有重要意义。
