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The “Nuclear Domains and Pathologies” team led by Jean-Jacques Diaz, Inserm Research Director at the Cancer Research Center of Lyon (Inserm/CNRS/Université Claude Bernard Lyon 1/Centre Léon Bérard), has recently demonstrated that one of the essential components of the “cellular machinery” that produces proteins – the ribosome – is altered in tumors. The researchers have observed that these modified ribosomes function differently in cancer cells, preferentially producing proteins that favor cancer cell proliferation and survival. This discovery opens up new possibilities for the development of innovative cancer therapies that target this abnormal machinery. This research has been published in Proceedings of the National Academy of Sciences (PNAS).
The research performed by Jean-Jacques Diaz and his team focuses on a key cell function: the production of proteins via “small specialist robots” called ribosomes. Their task is to retrieve coded genetic messages and decode them in the form of active proteins. These proteins then go on to play roles in various physiological mechanisms of the body, such as the insulin involved in blood glucose control.
The abnormally high metabolic activity and proliferation of cancer cells require the production of additional protein. In a major study published in Cancer Cell in 2013, the researchers identified certain ribosomal modifications that occur during the development of breast and colon cancers, and which promote the development of these diseases. In the study published this month in PNAS, coordinated by CNRS Research Officer Frédéric Catez, the team in Lyon demonstrated the mechanism by which these ribosomal modifications (2′-O-methylations) alter protein synthesis.More specifically, the researchers are interested in the role played by ribosomes in cancer.
More particularly, they demonstrate that the plasticity of 2′-O-methylation modifies ribosome functioning. This discovery reveals a new facet of the ribosome, that of a direct regulator of protein synthesis, whereas up until now it was considered to be just an effector.
This research opens up new possibilities for using ribosomes, particularly in oncology. By providing a precise description, at the molecular level, of the ribosomes in the tumor cells of various cancers, this work opens up as yet unexplored research avenues for the identification of new prognostic markers of tumor development and for the development of new therapies targeted against these specific ribosomes. These avenues are currently being explored by the team from the Cancer Research Center of Lyon (CRCL).
 Marcel, V. et al. Cancer Cell. 2013. 24(3):318-30)
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“Evidence for rRNA 2′-O-methylation plasticity: control of intrinsic translational capabilities of human ribosomes”
Jenny Erales1, Virginie Marchand2, Baptiste Panthu3,4, Sandra Gillot5, Stéphane Belin1,9, Sandra E. Ghayad1,10, Maxime Garcia1, Florian Laforêts1, Virginie Marcel1, Agnès Baudin-Baillieu5, Pierre Bertin5, Yohann Coute6, Annie Adrait6, Mélanie Meyer7, Gabriel Therizols1,11, Marat Yusupov7, Olivier Namy5, Théophile Ohlmann3,4, Yuri Motorin8, Frédéric Catez1* and Jean-Jacques Diaz1*
1Université de Lyon, Centre de Recherche en Cancérologie de Lyon UMR Inserm 1052 CNRS 5286, Centre Léon Bérard, F-69373, Lyon, France.
2 Plateforme de Séquençage à Haut Débit (NGS), FR3209 BMCT CNRS – Université de Lorraine, F-54505, Vandoeuvre-les-Nancy, France.
3Centre International de Recherche en Infectiologie, Université de Lyon, Lyon, France.
4Ecole Normale Supérieure de Lyon, France.
5Institut de Biologie Intégrative de la cellule (I2BC), CEA, CNRS, Université Paris-Sud, Université Paris-Saclay, France.
6Université Grenoble Alpes, Commissariat à l’énergie atomique et aux énergies alternatives, Inserm, Institut de Biosciences et Biotechnologies de Grenoble, Laboratoire Biologie à Grande Échelle, 38000 Grenoble, France.
7Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS UMR 7104 Inserm U 964, Illkirch F-67404, France.
8Ingénierie Moléculaire et Physiopathologie Articulaire. UMR7365 CNRS, Université de Lorraine, Vandoeuvre-les-Nancy, F-54505, France.
9Adresse actuelle : Grenoble Institut des Neurosciences, GIN, Univ. Grenoble Alpes, F-38000 Grenoble, France.
10Adresse actuelle: Department of Biology, Faculty of Science II, Lebanese University, Fanar, Lebanon.
11Adresse actuelle : Department of Urology, University of California, San Francisco, San Francisco, United States.
PNAS : doi:10.1073/pnas.1707674114