Professor and Director
Département de biochimie
P 514 343-6372
Staufen1: The goal of the research is to decipher the mechanisms by which post-transcriptional gene regulation influences cell proliferation and how its deregulation may lead to cancer. We focus on the roles of the RNA-binding protein Staufen1 in relation to its capacity to interact with cell cycle regulators and modulate cell proliferation in cancer cells. This research has the great potential to advance health-related knowledge through the discovery of novel pathways that control cell proliferation and the understanding of Stau1-cell cycle regulator interaction that may lead to the development of new drugs for cancer treatments.
Cell division is a highly controlled process with several checkpoints that control exit/entry into successive phases of the cell cycle. These processes require the differential expression of many critical cell-cycle effectors. Post-transcriptional regulation of mRNAs is a perfect mechanism to properly link protein synthesis to cell needs with high precision. In this context, we published ground-breaking results that established Stau1 as a major regulator of transport, decay, differential splicing and translation of many RNA transcripts. We further showed that many of them code for proteins involved in cell cycle regulation. The importance of Stau1 was confirmed by the fact that its expression decreases during mitosis due to its interaction with the cell cycle regulator E3 ubiquitin ligase APC/C and that expression of Stau155-FLAG3 in transformed cells affects mitosis entry and impairs proliferation. Importantly, these phenotypes were not observed in non-transformed cells. In contrast, Stau1 down-regulation halts cell cycle progression of untransformed cells but not transformed cells. Our hypotheses are Stau1 controls the fate of bound-mRNAs involved in the regulation of cell proliferation and that its functions are modulated by interaction with cell cycle regulators. Remarkably, this mechanism is impaired in cancer cells, contributing to their deregulated cell division. Thus our study on Stau1 will allow us to tackle cancers from an innovative angle.
Staufen2: We also want to understand the importance of post-transcriptional regulation of gene expression in DNA damages and apoptosis. We recently made an important advance by showing that the endogenous expression of Staufen2 (Stau2) is down-regulated in response to DNA damaging agents. The human Stau2 is an RNA-binding protein and a major regulator of mRNA transport, decay and translation. We recently showed that Stau2 is an anti-apoptotic protein that could be involved in DNA replication and/or maintenance of genome integrity and that its expression is regulated by E2F1 via the ATR signaling pathway. Strikingly, Stau2 down-regulation enhances levels of DNA damage and promotes apoptosis in CPT-treated cells. In this project, we want to identify the signalling pathway that links DNA damages to Stau2 down-regulation and find the role of Stau2 and Stau2-bound mRNAs in the DNA damage response.
Major ongoing projects :
Our ongoing projects aim to :
- Zhang, X., Trepanier, V., Beaujois, R., Viranaicken, W., Drobetsky, E., and DesGroseillers, L. (2016) Down-regulation of Staufen2 expression in response to DNA damages facilitates apoptosis. Nucl. Acid Res. doi: 10.1093/nar/gkw057
- Boulay, K., Ghram, M., Viranaicken, W., Trépanier, V., Mollet, S., Fréchina, C., and DesGroseillers, L. (2014) Cell cycle-dependent regulation of the RNA-binding protein Staufen1. Nucl. Acid Res 42, 7867-7883.
- Ravel-Chapuis, A., Bélanger, B., Yadava, R.S., Mahadevan, M.S., DesGroseillers, L., Côté, J., and Jasmin, B.J. (2012) The RNA-binding protein Staufen1 is increased in DM1 skeletal muscle and promotes alternative pre-mRNA splicing. J. Cell Biol. 196, 699-712
- Lebeau, G., Miller, L.C., Tartas, M., McAdam, R., Laplante, I., Badeaux, F., DesGroseillers, L., Sossin, W.S., and Lacaille, J.-C. (2011) Staufen 2 regulates mGluR long-term depression and Map1b mRNA distribution in hippocampal pyramidal cells. Learning and Memory 18, 314-326.
- Bidinosti, M., Ran, I., Sanchez-Carbente, M.R., Martineau, Y., Gingras, A.-C., Gkogkas, C., Raught, B., Bramham, C., Sossin, W.A., Costa-Mattioli, M., DesGroseillers, L., Lacaille, J.C., and Sonenberg, N. (2010) Postnatal deamidation of 4E-BP2 in brain enhances its association with Raptor and alters kinetics of excitatory synaptic transmission. Mol Cell. 37, 797-808.
- Lebeau, G., Maher-Laporte, M., Topolnik, L., Laurent, C.E., Sossin, W.S., DesGroseillers L., and Lacaille, J.-C. (2008). Staufen1 regulation of protein synthesis-dependent long-term potentiation and synaptic function in hippocampal pyramidal cells. Mol. Cell. Biol. 28, 2896-2907.
- Kim, Y.K., Furic, L., Parisien, M., Major, F., DesGroseillers, L., and Maquat, L.E. (2007). Staufen1 Regulates Diverse Classes of Mammalian Transcripts. EMBO J 26, 2670-2681.
- Elvira, G., Wasiak, S., Blandford, V., Tong, X.K., Serrano, A., Fan, X., Sanchez-Carbente, M.R., Servant, F., Bell, A.W., Boismenu, D., Lacaille, J.-C., McPherson, P.S., DesGroseillers, L. and Sossin, W.S. (2006). Characterization of an RNA granule from developing brain. Mol. Cell. Proteomics 5, 635-651.
- Kim, Y.K., Furic, L., DesGroseillers, L., and Maquat, L.E. (2005). Mammalian Staufen1 Recruits Upf1 to Specific mRNA 3’UTRs so as to Elicit mRNA Decay. Cell 120, 195-208.