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.
Highlights
Margalida Rosselló-Tortellaa,b, Pere Llinàs-Ariasa, Yuriko Sakaguchic, Kenjyo Miyauchi (宮内健常)c, Veronica Davalosa, Fernando Setiena, Maria E
We report that the Transfer RNA (tRNA)-yW Synthesizing Protein 2 (TYW2) undergoes promoter hypermethylation-associated transcriptional silencing in human cancer, in colorectal tumors
To identify epigenetic defects in the enzymes involved in generating the hypermodified guanosine nucleotide in the tRNAPhe, we studied the DNA methylation status of the 5′-end–associated CpG islands of TRMT5, TYW1, TYW2, TYW3, TYW4, and TYW5 genes
Summary
Margalida Rosselló-Tortellaa,b , Pere Llinàs-Ariasa, Yuriko Sakaguchic, Kenjyo Miyauchi (宮内健常)c , Veronica Davalosa , Fernando Setiena , Maria E. 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. 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 methylationassociated 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. Defects in tRNA modifications or tRNA modifier enzymes are present in various human pathologies, including neurologic disorders, mitochondrial diseases, and cancers [8,9,10]
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