TRM6/61 connects PKCα with translational control through tRNAiMet stabilization: impact on tumorigenesis

Françoise Macari (1, 2) , Y El-Houfi (2, 1) , G Boldina (3, 4) , Hao Xu (5) , S Khoury-Hanna (2, 1) , Jérémy Ollier (2, 1) , Laura Yazdani (2, 1) , Gang Zheng (6) , I Bièche (7) , Noémie Legrand (2, 1) , Damien Paulet (8) , S Durrieu (9, 10) , A Byström (5) , Stéphane Delbecq (11) , Bernard Lapeyre (12, 13) , L Bauchet (14) , Julie Pannequin (2, 1) , Frédéric Hollande (2, 15) , T Pan (6) , M Teichmann (9) , S Vagner (3, 4) , Alexandre David (2, 1) , Armelle Choquet (2, 1) , Dominique Joubert (2, 1)

1 UM - Université de Montpellier
2 IGF - Institut de Génomique Fonctionnelle
3 Stress génotoxiques et cancer
4 PSL - Université Paris Sciences et Lettres
5 Department of Molecular Biology [Umeå]
6 Department of Biochemistry and Molecular Biology
7 CRLCC René Huguenin - CRLCC René Huguenin
8 MAB - Méthodes et Algorithmes pour la Bioinformatique
9 Institut Européen de Chimie et de Biologie
10 UMR TETIS - Territoires, Environnement, Télédétection et Information Spatiale
11 LBCM - Vaccination Antiparasitaire : Laboratoire de Biologie Cellulaire et Moléculaire
12 CRIOBE - Centre de recherches insulaires et observatoire de l'environnement
13 CRBM - Centre de recherche en Biologie cellulaire de Montpellier
14 Neurochirurgie [Hôpital Gui de Chauliac]
15 Molecular Mechanisms of Tumor Progression Laboratory

Accumulating evidence suggests that changes of the protein synthesis machinery alter translation of specific mRNAs and participate in malignant transformation. Here we show that protein kinase C α (PKCα) interacts with TRM61, the catalytic subunit of the TRM6/61 tRNA methyltransferase. The TRM6/61 complex is known to methylate the adenosine 58 of the initiator methionine tRNA (tRNAiMet), a nuclear post-transcriptional modification associated with the stabilization of this crucial component of the translation-initiation process. Depletion of TRM6/61 reduced proliferation and increased death of C6 glioma cells, effects that can be partially rescued by overexpression of tRNAiMet. In contrast, elevated TRM6/61 expression regulated the translation of a subset of mRNAs encoding proteins involved in the tumorigenic process and increased the ability of C6 cells to form colonies in soft agar or spheres when grown in suspension. In TRM6/61/tRNAiMet-overexpressing cells, PKCα overexpression decreased tRNAiMet expression and both colony- and sphere-forming potentials. A concomitant increase in TRM6/TRM61 mRNA and tRNAiMet expression with decreased expression of PKCα mRNA was detected in highly aggressive glioblastoma multiforme as compared with Grade II/III glioblastomas, highlighting the clinical relevance of our findings. Altogether, we suggest that PKCα tightly controls TRM6/61 activity to prevent translation deregulation that would favor neoplastic development.

Domaines: Sciences de l'ingénieur [physics]

Françoise Macari, Y El-Houfi, G Boldina, Hao Xu, S Khoury-Hanna, et al.. TRM6/61 connects PKCα with translational control through tRNAiMet stabilization: impact on tumorigenesis. Oncogene, 2016, 35 (14), pp.1785-1796. ⟨10.1038/onc.2015.244⟩. ⟨hal-01224206⟩