tRNA modifications at the anti‐codon loop are critical for accurate decoding. FTSJ1 was hypothesized to be a human tRNA 2′‐O‐methyltransferase. tRNA^Phe(GAA) from intellectual disability patients with mutations in ftsj1 lacks 2′‐O‐methylation at C32 and G34 (Cm32 and Gm34). However, the catalytic activity, RNA substrates, and pathogenic mechanism of FTSJ1 remain unknown, owing, in part, to the difficulty in reconstituting enzymatic activity in vitro . Here, we identify an interacting protein of FTSJ1, WDR6. For the first time, we reconstitute the 2′‐O‐methylation activity of the FTSJ1‐WDR6 complex in vitro , which occurs at position 34 of specific tRNAs with m¹G37 as a prerequisite. We find that modifications at positions 32, 34, and 37 are interdependent and occur in a hierarchical order in vivo . We also show that the translation efficiency of the UUU codon, but not the UUC codon decoded by tRNA^Phe(GAA), is reduced in ftsj1 knockout cells. Bioinformatics analysis reveals that almost 40% of the high TTT‐biased genes are related to brain/nervous functions. Our data potentially enhance our understanding of the relationship between FTSJ1 and nervous system development.

中文翻译：

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智力障碍相关基因 ftsj1 负责特定 tRNA 的 2'-O-甲基化。

反密码子环上的 tRNA 修饰对于准确解码至关重要。FTSJ1 被假设为人类 tRNA 2'-O-甲基转移酶。来自ftsj1突变的智力障碍患者的tRNA ^Phe (GAA)在 C32 和 G34（Cm32 和 Gm34）处缺乏 2'-O-甲基化。然而，FTSJ1 的催化活性、RNA 底物和致病机制仍然未知，部分原因是体外重建酶活性的困难。在这里，我们鉴定了 FTSJ1 的一个相互作用蛋白 WDR6。我们首次在体外重建了 FTSJ1-WDR6 复合物的 2'-O-甲基化活性，该活性发生在特定 tRNA 的 34 位，以 m ¹ G37 为先决条件。我们发现第 32、34 和 37 位的修饰是相互依赖的，并且在体内以分层顺序发生。我们还表明，在ftsj1敲除细胞中，UUU 密码子的翻译效率降低，但 tRNA ^Phe (GAA)解码的 UUC 密码子的翻译效率没有降低。生物信息学分析表明，近 40% 的高 TTT 偏向基因与大脑/神经功能相关。我们的数据可能会增强我们对 FTSJ1 与神经系统发育之间关系的理解。