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

Maxime Janin, Vanessa Ortiz-Barahona, Manuel Castro de Moura, Anna Martínez-Cardús, Pere Llinàs-Arias, Marta Soler, Daphna Nachmani, Joffrey Pelletier, Ulrike Schumann, Maria E. Calleja-Cervantes, Sebastian Moran, Sonia Guil, Alberto Bueno-Costa, David Piñeyro, Montserrat Perez-Salvia, Margalida Rosselló-Tortella, Laia Piqué, Joan J. Bech-Serra, Carolina De La Torre, August VidalMaría Martínez-Iniesta, Juan F. Martín-Tejera, Alberto Villanueva, Alexandra Arias, Isabel Cuartas, Ana M. Aransay, Andres Morales La Madrid, Angel M. Carcaboso, Vicente Santa-Maria, Jaume Mora, Agustin F. Fernandez, Mario F. Fraga, Iban Aldecoa, Leire Pedrosa, Francesc Graus, Noemi Vidal, Fina Martínez-Soler, Avelina Tortosa, Cristina Carrato, Carme Balañá, Matthew W. Boudreau, Paul J. Hergenrother, Peter Kötter, Karl Dieter Entian, Jürgen Hench, Stephan Frank, Sheila Mansouri, Gelareh Zadeh, Pablo D. Dans, Modesto Orozco, George Thomas, Sandra Blanco, Joan Seoane, Thomas Preiss, Pier Paolo Pandolfi, Manel Esteller

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1053-1074
Number of pages22
JournalActa Neuropathologica
Volume138
Issue number6
DOIs
StatePublished - Dec 1 2019

Fingerprint

Methyltransferases
Ribosomes
Epigenomics
Glioma
RNA
5-Methylcytosine
Survival
DNA Methylation
Proteome
Transcriptome
Neoplasms
Enzymes
Proteins

Keywords

  • Clinical outcome
  • Epitranscriptomics
  • Glioma
  • RNA methylation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

Janin, M., Ortiz-Barahona, V., de Moura, M. C., Martínez-Cardús, A., Llinàs-Arias, P., Soler, M., ... Esteller, M. (2019). Epigenetic loss of RNA-methyltransferase NSUN5 in glioma targets ribosomes to drive a stress adaptive translational program. Acta Neuropathologica, 138(6), 1053-1074. https://doi.org/10.1007/s00401-019-02062-4

Epigenetic loss of RNA-methyltransferase NSUN5 in glioma targets ribosomes to drive a stress adaptive translational program. / Janin, Maxime; Ortiz-Barahona, Vanessa; de Moura, Manuel Castro; Martínez-Cardús, 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; Esteller, Manel.

In: Acta Neuropathologica, Vol. 138, No. 6, 01.12.2019, p. 1053-1074.

Research output: Contribution to journalArticle

Janin, M, Ortiz-Barahona, V, de Moura, MC, Martínez-Cardús, A, Llinàs-Arias, P, Soler, M, Nachmani, D, Pelletier, J, Schumann, U, Calleja-Cervantes, ME, Moran, S, Guil, S, Bueno-Costa, A, Piñeyro, D, Perez-Salvia, M, Rosselló-Tortella, M, Piqué, L, Bech-Serra, JJ, De La Torre, C, Vidal, A, Martínez-Iniesta, M, Martín-Tejera, JF, Villanueva, A, Arias, A, Cuartas, I, Aransay, AM, La Madrid, AM, Carcaboso, AM, Santa-Maria, V, Mora, J, Fernandez, AF, Fraga, MF, Aldecoa, I, Pedrosa, L, Graus, F, Vidal, N, Martínez-Soler, F, Tortosa, A, Carrato, C, Balañá, C, Boudreau, MW, Hergenrother, PJ, Kötter, P, Entian, KD, Hench, J, Frank, S, Mansouri, S, Zadeh, G, Dans, PD, Orozco, M, Thomas, G, Blanco, S, Seoane, J, Preiss, T, Pandolfi, PP & Esteller, M 2019, 'Epigenetic loss of RNA-methyltransferase NSUN5 in glioma targets ribosomes to drive a stress adaptive translational program', Acta Neuropathologica, vol. 138, no. 6, pp. 1053-1074. https://doi.org/10.1007/s00401-019-02062-4
Janin M, Ortiz-Barahona V, de Moura MC, Martínez-Cardús A, Llinàs-Arias P, Soler M et al. Epigenetic loss of RNA-methyltransferase NSUN5 in glioma targets ribosomes to drive a stress adaptive translational program. Acta Neuropathologica. 2019 Dec 1;138(6):1053-1074. https://doi.org/10.1007/s00401-019-02062-4
Janin, Maxime ; Ortiz-Barahona, Vanessa ; de Moura, Manuel Castro ; Martínez-Cardús, 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 ; Esteller, Manel. / Epigenetic loss of RNA-methyltransferase NSUN5 in glioma targets ribosomes to drive a stress adaptive translational program. In: Acta Neuropathologica. 2019 ; Vol. 138, No. 6. pp. 1053-1074.
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AU - Janin, Maxime

AU - Ortiz-Barahona, Vanessa

AU - de Moura, Manuel Castro

AU - Martínez-Cardús, Anna

AU - Llinàs-Arias, Pere

AU - Soler, Marta

AU - Nachmani, Daphna

AU - Pelletier, Joffrey

AU - Schumann, Ulrike

AU - Calleja-Cervantes, Maria E.

AU - Moran, Sebastian

AU - Guil, Sonia

AU - Bueno-Costa, Alberto

AU - Piñeyro, David

AU - Perez-Salvia, Montserrat

AU - Rosselló-Tortella, Margalida

AU - Piqué, Laia

AU - Bech-Serra, Joan J.

AU - De La Torre, Carolina

AU - Vidal, August

AU - Martínez-Iniesta, María

AU - Martín-Tejera, Juan F.

AU - Villanueva, Alberto

AU - Arias, Alexandra

AU - Cuartas, Isabel

AU - Aransay, Ana M.

AU - La Madrid, Andres Morales

AU - Carcaboso, Angel M.

AU - Santa-Maria, Vicente

AU - Mora, Jaume

AU - Fernandez, Agustin F.

AU - Fraga, Mario F.

AU - Aldecoa, Iban

AU - Pedrosa, Leire

AU - Graus, Francesc

AU - Vidal, Noemi

AU - Martínez-Soler, Fina

AU - Tortosa, Avelina

AU - Carrato, Cristina

AU - Balañá, Carme

AU - Boudreau, Matthew W.

AU - Hergenrother, Paul J.

AU - Kötter, Peter

AU - Entian, Karl Dieter

AU - Hench, Jürgen

AU - Frank, Stephan

AU - Mansouri, Sheila

AU - Zadeh, Gelareh

AU - Dans, Pablo D.

AU - Orozco, Modesto

AU - Thomas, George

AU - Blanco, Sandra

AU - Seoane, Joan

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AU - Pandolfi, Pier Paolo

AU - Esteller, Manel

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