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

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.

Stressin’ and slicin’: stress‐induced tRNA fragmentation codon‐adapts translation to repress cell growth

“…In conclusion, the recent study by Huh et al (2020) 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.…”

“…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 codonbased stress response that fine-tunes translation to restrain growth in human cells.…”

“…Although still little is known about the function of tRFs, exciting studies suggest that specific fragments perturb mRNA stability and repress translation through critical interactions with RNA binding proteins (RBPs) and translation initiation factors (Ivanov et al, 2011;Goodarzi et al, 2015;Guzzi et al, 2018). Huh et al (2020) expand the tRF-protein interactome by uncovering selective binding between tRF Tyr GUA and two RBPs with multiple roles in RNA regulation, namely hnRNPA1 and La/SSB, in response to oxidative stress. Intriguingly, tRF Tyr GUA may directly compete for hnRNPA1 binding with specific growthassociated mRNA subsets, promoting their destabilization under stress conditions.…”

tRNA-derived small RNAs: novel regulators of cancer hallmarks and targets of clinical application

“…One year later, another study published in the same journal showed that abnormally expressed tRF-related mRNAs were also correlated with glycolysis and ATP synthesis in almost all solid tumor types [ 84 ]. Moreover, other studies have also suggested the role of tRFs in protein biosynthesis in normal or tumor cells [ 32 , 85 ].…”

Emerging Classes of Small Non-Coding RNAs With Potential Implications in Diabetes and Associated Metabolic Disorders

“…Both pre-tRNAs and mature tRNAs can be fragmented in concert with tRNA expression, or in response to a stress stimulus (53)(54)(55)(56). While the nomenclature of tRFs is not yet well established, six main classes of tRFs have been described.…”