Epigenetic loss of RNA-methyltransferase NSUN5 in glioma targets ribosomes to drive a stress adaptive translational program

TitleEpigenetic loss of RNA-methyltransferase NSUN5 in glioma targets ribosomes to drive a stress adaptive translational program
Publication TypeJournal Article
Year of Publication2019
AuthorsJanin, Maxime, Ortiz-Barahona Vanessa, de Moura Manuel Castro, Martinez-Cardus Anna, Llinàs-Arias Pere, Soler Marta, Nachmani Daphna, Pelletier Joffrey, Schumann Ulrike, Calleja-Cervantes Maria E., Moran Sebastian, Guil Sonia, Bueno-Costa Alberto, Piñeyro David, Perez-Salvia Montserrat, Rosselló-Tortella Margalida, Piqué Laia, Bech-Serra Joan J., De La Torre Carolina, Vidal August, Martínez-Iniesta María, Martín-Tejera Juan F., Villanueva Alberto, Arias Alexandra, Cuartas Isabel, Aransay Ana M., La Madrid Andres Morales, Carcaboso Angel M., Santa-Maria Vicente, Mora Jaume, Fernandez Agustin F., Fraga Mario F., Aldecoa Iban, Pedrosa Leire, Graus Francesc, Vidal Noemi, Martínez-Soler Fina, Tortosa Avelina, Carrato Cristina, Balañá Carme, Boudreau Matthew W., Hergenrother Paul J., Kötter Peter, Entian Karl-Dieter, Hench Jürgen, Frank Stephan, Mansouri Sheila, Zadeh Gelareh, Dans Pablo D., Orozco Modesto, Thomas George, Blanco Sandra, Seoane Joan, Preiss Thomas, Pandolfi Pier Paolo, and Esteller Manel
JournalActa neuropathologica
Pagination1053 - 1074
Date Published12/2019
ISBN Number1432-05330001-6322
KeywordsClinical outcome, Epitranscriptomics, Glioma, RNA methylation

Tumors have aberrant proteomes that often do not match their corresponding transcriptome profiles. One possible cause of this discrepancy is the existence of aberrant RNA modification landscapes in the so-called epitranscriptome. Here, we report that human glioma cells undergo DNA methylation-associated epigenetic silencing of NSUN5, a candidate RNA methyltransferase for 5-methylcytosine. In this setting, NSUN5 exhibits tumor-suppressor characteristics in vivo glioma models. We also found that NSUN5 loss generates an unmethylated status at the C3782 position of 28S rRNA that drives an overall depletion of protein synthesis, and leads to the emergence of an adaptive translational program for survival under conditions of cellular stress. Interestingly, NSUN5 epigenetic inactivation also renders these gliomas sensitive to bioactivatable substrates of the stress-related enzyme NQO1. Most importantly, NSUN5 epigenetic inactivation is a hallmark of glioma patients with long-term survival for this otherwise devastating disease.

Short TitleActa Neuropathol