Stressin' and slicin': stress-induced tRNA fragmentation codon-adapts translation to repress cell growth

Abstract

Transfer RNAs (tRNAs) are central adaptors that decode genetic information during translation and have been long considered static cellular components. However, whether dynamic changes in tRNAs and tRNA-derived fragments actively contribute to gene regulation remains debated. In this issue, Huh et al (2020) highlight tyrosine tRNA_GUA fragmentation at the nexus of an evolutionarily conserved adaptive codon-based stress response that fine-tunes translation to restrain growth in human cells.

Figure 1. Stress‐induced tyrosine tRNA fragmentation controls cell growth

Schematic model depicts the adaptive codon‐based stress response governed by tyrosine tRNA^Tyr _GUA fragmentation in human cells. Through an unknown mechanism, oxidative stress induces rapid depletion of pre‐tRNA^Tyr _GUA and accumulation of tRNA fragments (tRF^Tyr _GUA) in an exoribonuclease DIS3L2‐dependent manner. Left, tRF^Tyr _GUA competes for hnRNPA1 binding with specific growth‐associated mRNA subsets promoting their destabilization. Right, pre‐tRNA^Tyr _GUA fragmentation subsequently depletes mature tRNA^Tyr _GUA, thereby hampering the translation of growth‐related mRNAs (e.g., USP3, EPCAM, and SCD) that are enriched in tyrosine codons. The synergistic effects on the transcriptome and translatome induced by the accumulation of tRF^Tyr _GUA and depletion of tRNA^Tyr _GUA drive an evolutionarily conserved program that limits cell growth upon oxidative stress.