Eukaryotic transfer RNAs can become selectively fragmented upon various stresses, generating tRNA‐derived small RNA fragments. Such fragmentation has been reported to impact a small fraction of the tRNA pool and thus presumed to not directly impact translation. We report that oxidative stress can rapidly generate tyrosine‐tRNA_GUA fragments in human cells—causing significant depletion of the precursor tRNA. Tyrosine‐tRNA_GUA depletion impaired translation of growth and metabolic genes enriched in cognate tyrosine codons. Depletion of tyrosine tRNA_GUA or its translationally regulated targets USP3 and SCD repressed proliferation—revealing a dedicated tRNA‐regulated growth‐suppressive pathway for oxidative stress response. Tyrosine fragments are generated in a DIS3L2 exoribonuclease‐dependent manner and inhibit hnRNPA1‐mediated transcript destabilization. Moreover, tyrosine fragmentation is conserved in C. elegans. Thus, tRNA fragmentation can coordinately generate trans‐acting small RNAs and functionally deplete a tRNA. Our findings reveal the existence of an underlying adaptive codon‐based regulatory response inherent to the genetic code.

中文翻译：

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应激诱导的酪氨酸-tRNA耗竭反应介导基于密码子的翻译抑制和生长抑制

真核转移 RNA 可以在各种应激下选择性片段化，产生 tRNA 衍生的小 RNA 片段。据报道，这种碎片会影响 tRNA 库的一小部分，因此推测不会直接影响翻译。我们报告说，氧化应激可以在人体细胞中快速生成酪氨酸-tRNA _GUA片段，从而导致前体 tRNA 显着消耗。酪氨酸-tRNA _GUA缺失会损害富含同源酪氨酸密码子的生长和代谢基因的翻译。酪氨酸 tRNA _GUA或其翻译调节靶点 USP3 和 SCD 的耗尽抑制了增殖——揭示了氧化应激反应的专用 tRNA 调节生长抑制途径。酪氨酸片段以 DIS3L2 核糖核酸外切酶依赖性方式生成，并抑制 hnRNPA1 介导的转录物不稳定。此外，酪氨酸断裂在秀丽隐杆线虫中是保守的。因此，tRNA 片段化可以协调生成反式作用小 RNA 并在功能上耗尽 tRNA。我们的研究结果揭示了遗传密码固有的基于适应性密码子的调节反应的存在。