RT Journal Article SR Electronic T1 An adaptive stress-induced tRNA depletion response mediates codon-based gene repression and growth suppression JF bioRxiv FD Cold Spring Harbor Laboratory SP 416727 DO 10.1101/416727 A1 Doowon Huh A1 Maria C. Passarelli A1 Lisa Fish A1 Henrik Molina A1 Elizabeth A. McMillan A1 Hani Goodarzi A1 Sohail F. Tavazoie YR 2018 UL http://biorxiv.org/content/early/2018/09/13/416727.abstract AB 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 tRNAGUA—causing significant depletion of the precursor tRNA molecule. Tyrosyl tRNAGUA depletion impaired expression of a gene-set enriched in its cognate tyrosine codons, comprising growth and metabolic genes. Depletion of tyrosyl tRNAGUA 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 HIGHLIGHTSStress-induced tyrosyl tRNAGUA fragmentation depletes precursor tRNATyrGUA and mature tRNATyrGUATRNATyrGUA depletion impairs expression of growth genes enriched in cognate tyrosine codonsThis constitutes a growth suppressive adaptive stress response driven by codon-based logic