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

EMBO J. 2021 Jan 15;40(2):e106696. doi: 10.15252/embj.2020106696. Epub 2020 Dec 21.

Abstract

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.

Keywords: hnRNPA1; oxidative stress; tRNA; tRNA fragments; translation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Caenorhabditis elegans / genetics
  • Cell Line
  • Cell Proliferation / genetics
  • Codon / genetics*
  • HEK293 Cells
  • Humans
  • Oxidative Stress / genetics
  • Protein Biosynthesis / genetics*
  • RNA, Transfer / genetics*
  • Tyrosine / genetics*
  • Ubiquitin-Specific Proteases / genetics

Substances

  • Codon
  • Tyrosine
  • RNA, Transfer
  • Ubiquitin-Specific Proteases