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Title: Epigenetic loss of the transfer RNA-modifying enzyme TYW2 induces ribosome frameshifts in colon cancer
Author: Rosselló Tortella, Margalida
Llinàs Arias, Pere
Sakaguchi, Yuriko
Miyauchi, Kenjyo
Davalos, Veronica
Setién, Fernando
Calleja Cervantes, Maria E.
Pineyro, David
Martínez Gomez, Jesús
Guil, Sonia
Joshi, Ricky
Villanueva Garatachea, Alberto
Suzuki, Tsutomu
Esteller, Manel
Keywords: Càncer colorectal
Colorectal cancer
Issue Date: 25-Aug-2020
Publisher: National Academy of Sciences
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 RNA5 (mRNA5). 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.
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It is part of: Proceedings of The National Academy of Sciences of The United States of America, 2020, vol. 117, num. 34, p. 20785-20793
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Appears in Collections:Articles publicats en revistes (Ciències Fisiològiques)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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