An adaptive stress-induced tRNA depletion response mediates codon-based gene repression and growth suppression

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.