Institut für Biologie, Molekulare Zellbiologie, Humboldt-Universität zu Berlin, Berlin, Germany.
Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany.
Nucleic Acids Res. 2019 Apr 23;47(7):3711-3727. doi: 10.1093/nar/gkz063.
In eukaryotes, the wobble position of tRNA with a GUN anticodon is modified to the 7-deaza-guanosine derivative queuosine (Q34), but the original source of Q is bacterial, since Q is synthesized by eubacteria and salvaged by eukaryotes for incorporation into tRNA. Q34 modification stimulates Dnmt2/Pmt1-dependent C38 methylation (m5C38) in the tRNAAsp anticodon loop in Schizosaccharomyces pombe. Here, we show by ribosome profiling in S. pombe that Q modification enhances the translational speed of the C-ending codons for aspartate (GAC) and histidine (CAC) and reduces that of U-ending codons for asparagine (AAU) and tyrosine (UAU), thus equilibrating the genome-wide translation of synonymous Q codons. Furthermore, Q prevents translation errors by suppressing second-position misreading of the glycine codon GGC, but not of wobble misreading. The absence of Q causes reduced translation of mRNAs involved in mitochondrial functions, and accordingly, lack of Q modification causes a mitochondrial defect in S. pombe. We also show that Q-dependent stimulation of Dnmt2 is conserved in mice. Our findings reveal a direct mechanism for the regulation of translational speed and fidelity in eukaryotes by a nutrient originating from bacteria.
在真核生物中，具有 GUN 反密码子的 tRNA 的摆动位置被修饰为 7-脱氮鸟苷衍生物 Queuosine（Q），但 Q 的原始来源是细菌，因为 Q 是由真细菌合成并被真核生物回收用于掺入 tRNA。Q34 修饰刺激 Dnmt2/Pmt1 依赖性 tRNAAsp 反密码子环中的 C38 甲基化（m5C38）在裂殖酵母中。在这里，我们通过裂殖酵母的核糖体分析显示，Q 修饰增强了天冬氨酸（GAC）和组氨酸（CAC）的 C 末端密码子的翻译速度，并降低了天冬酰胺（AAU）和酪氨酸（UAU）的 U 末端密码子的翻译速度，从而平衡了全基因组范围内 Q 密码子的翻译。此外，Q 通过抑制甘氨酸密码子 GGC 的第二位置错读而不是摆动错读来防止翻译错误。缺乏 Q 会导致与线粒体功能相关的 mRNA 翻译减少，因此，Q 修饰的缺乏会导致裂殖酵母的线粒体缺陷。我们还表明，Q 依赖性刺激 Dnmt2 在小鼠中是保守的。我们的发现揭示了一种由细菌来源的营养素调节真核生物翻译速度和保真度的直接机制。
