Epigenetic loss of the transfer RNA-modifying enzyme TYW2 induces ribosome frameshifts in colon cancer

Abstract

Transfer RNA (tRNA) activity is tightly regulated to provide a physiological protein translation, and tRNA chemical modifications control its function in a complex with ribosomes and messenger RNAs (mRNAs). In this regard, the correct hypermodification of position G37 of phenylalanine-tRNA, adjacent to the anticodon, is critical to prevent ribosome frameshifting events. Here we report that the tRNA-yW Synthesizing Protein 2 (TYW2) undergoes promoter hypermethylation-associated transcriptional silencing in human cancer, particularly in colorectal tumors. The epigenetic loss of TYW2 induces guanosine hypomodification in phenylalanine-tRNA, an increase in −1 ribosome frameshift events, and down-regulation of transcripts by mRNA decay, such as of the key cancer gene ROBO1. Importantly, TYW2 epigenetic inactivation is linked to poor overall survival in patients with early-stage colorectal cancer, a finding that could be related to the observed acquisition of enhanced migration properties and epithelial-to-mesenchymal features in the colon cancer cells that harbor TYW2 DNA methylation-associated loss. These findings provide an illustrative example of how epigenetic changes can modify the epitranscriptome and further support a role for tRNA modifications in cancer biology.

The nature of the modification at position 37 of tRNAPhe correlates with acquired taxol resistance

“…Extending from these findings, it may be inferred that the frameshifting efficiency of imG-14 in taxol resistant strains is theoretically higher than OHyW in wide type cells. Moreover, the latest study showed that loss of TYW2 increases the -1 programmed ribosome frameshifting frequency and is associated with poor survival in colorectal cancer patients ( 62 ). Taken together, TYW2 downregulation induced chemotherapy (taxol)-resistance may be another possible explanation for poor clinical outcomes in patients.…”

tRNA Metabolism and Lung Cancer: Beyond Translation

“…The pathogenesis of cancer changes the tRNA modification chemistry, which occurs after oxidative stress ( Endres et al, 2019 ). Increasing evidence argues that tRNA modification and corresponding tRNA-modifying enzymes not only play an important role in translation but also are important signal molecules in the pathogenesis of cancer ( Rashad et al, 2020 ; Rosselló-Tortella et al, 2020 ; Zhang et al, 2020c ). Dong et al found that the modification profiles of tRNA in rapidly proliferating cancer cells were roughly the same, indicating that there was a proliferation-related modification regulation in rapidly proliferating cancer cells, and tRNA had a positive regulatory effect in rapidly proliferating cancer cells ( Dong et al, 2016 ).…”

Roles of tRNA metabolism in aging and lifespan

“…Of note, tRNAs will be cleaved into fragments with regulatory functions under stress conditions [4][5][6] . In general, normal tRNA metabolism is essential to maintain the stability and functions of tRNA molecules, while the defects in certain tRNA biogenesis proteins cause various human diseases, including cancer, neurological disorders, immunodeficiency, and diabetes mellitus [7][8][9][10] .…”