A stress-induced Tyrosine tRNA depletion response mediates codon-based translational repression and growth suppression

SUMMARY 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.