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‐tRNAGUA fragments in human cells—causing significant depletion of the precursor tRNA. Tyrosine‐tRNAGUA depletion impaired translation of growth and metabolic genes enriched in cognate tyrosine codons. Depletion of tyrosine tRNAGUA 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.

Utilization of specific codons varies between organisms. Cancer represents a model for understanding DNA sequence evolution and could reveal causal factors underlying codon evolution. We found that across human cancer, arginine codons are frequently mutated to other codons. Moreover, arginine limitation—a feature of tumor microenvironments—is sufficient to induce arginine codon–switching mutations in human colon cancer cells. Such DNA codon switching events encode mutant proteins with arginine residue substitutions. Mechanistically, arginine limitation caused rapid reduction of arginine transfer RNAs and the stalling of ribosomes over arginine codons. Such selective pressure against arginine codon translation induced an adaptive proteomic shift toward low-arginine codon–containing genes, including specific amino acid transporters, and caused mutational evolution away from arginine codons—reducing translational bottlenecks that occurred during arginine starvation. Thus, environmental availability of a specific amino acid can influence DNA sequence evolution away from its cognate codons and generate altered proteins.

Eukaryotic transfer RNAs can become selectively fragmented upon various stresses,generating tRNA-derived small RNA fragments (tRFs). Such tRNA fragmentation has been observed to impact a small fraction of the tRNA pool and thus presumed to not directly impact translation. We report that in human cells, oxidative stress can rapidly generate tRFs derived from tyrosyl tRNA GUA -causing significant depletion of the precursor tRNA molecule. Tyrosyl tRNA GUA depletion impaired expression of a gene-set enriched in its cognate tyrosine codons, comprising growth and metabolic genes. Depletion of tyrosyl tRNA GUA or its downstream genes EPCAM, SCD, or USP3 repressed proliferation-revealing a tRNA-regulated growth suppressive pathway for oxidative stress response. Thus, tRNA fragmentation can both deplete a precursor tRNA molecule with codon-dependent regulatory consequences and also generate small-RNAs that interact with RNA binding proteins. Our findings reveal the existence of an underlying adaptive codon-based gene-regulatory logic inherent to the genetic code. RESEARCH HIGHLIGHTS• Stress-induced tyrosyl tRNA GUA fragmentation depletes precursor tRNA Tyr GUA and mature tRNA Tyr GUA • TRNA Tyr GUA depletion impairs expression of growth genes enriched in cognate tyrosine codons • This constitutes a growth suppressive adaptive stress response driven by codon-based logic

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