TY - JOUR T1 - An adaptive stress-induced tRNA depletion response mediates codon-based gene repression and growth suppression JF - bioRxiv DO - 10.1101/416727 SP - 416727 AU - Doowon Huh AU - Maria C. Passarelli AU - Lisa Fish AU - Henrik Molina AU - Elizabeth A. McMillan AU - Hani Goodarzi AU - Sohail F. Tavazoie Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/09/13/416727.abstract N2 - 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 ER -