Jocelyn Côté, Ph.D.

Associate Professor & Canada Research Chair on RNA Metabolism in Health and Disease Center for Neuromuscular Disease Department of Cellular and Molecular Medicine, Rm. 3111a Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5 Tel.: (613) 562-5800 (8660) FAX: (613) 562-5434 E-mail: jcote@uottawa.ca

Research Interests:

There are many post-translational modifications that can occur on the amino acid side chains of cellular proteins including phosphorylation, acetylation and methylation. The modification that is most common and that has received the most attention is undoubtedly phosphorylation. It is now well known that phosphorylation regulates protein-protein interactions, intracellular localization, protein turnover as well as enzymatic activity. However, the largest single function attributed to protein phosphorylation on serine, threonine or tyrosine residues is the regulation and amplification of signal transduction cascades. The discovery of kinases, phosphatases, protein modules and antibodies that recognize phosphorylated proteins has permitted the charaterization of these signaling cascades.

Protein methylation can occur on several amino acids including lysine, histidine and arginine. My lab will focus on elucidating the various cellular roles of protein arginine methylation.

Project #1: A Role for Arginine Methylation in Spinal Muscular Atrophy. Autosomal recessive spinal muscular atrophy (SMA) is a disease that is amongst the leading genetic cause of infants death. It is characterized by degeneration and loss of spinal cord motor neurons. SMA is caused by disruption of the “survival of motor neurons” gene (Smn1). Similar to what is seen for several neuromuscular disease causative genes, SMN plays an essential role in RNA metabolism and has been involved in the assembly of various ribonucleoprotein (RNP) complexes as well as pre-mRNA splicing. Despite a large body of work towards clarifying the apparently ubiquitous functions of SMN, the molecular mechanisms that lead to motor neuron-specific pathologies and development of the SMA phenotype remain to be elucidated. Motor neurons may have a particular vulnerability to defects in RNA processing or alternatively, SMN might have a yet unknown specialized function in this cell type.

We have generated antibodies that can recognize methyl-arginines in proteins. Using these methyl-specific antibodies, we have shown that arginine methylation is important for pre-mRNA splicing and can regulate the localization of SMN into distinct nuclear organelles (Gems vs Cajal bodies) known to have a role in RNA metabolism. Moreover, we have shown that SMA patient cells mislocalize arginine methylated proteins. Finally, recent data also shows that SMN has more affinity for proteins that harbor methylated arginines. My lab will be using various cellular and molecular approaches to elucidate how arginine methylation can regulate the activities of SMN in motor neurons and how this relates to the development of the SMA phenotype. Knowledge of the full spectrum of SMN activities and how it is regulated will pave the way for the development of new strategies for therapeutic intervention.

Project #2: The Role of Arginine Methylation by PRMT1 Isoforms in Breast Cancer. It has been observed that an increase in arginine methylation of endogenous proteins correlated with the cell transformation. PRMT1, which is the major protein arginine methyltransferase in mammals, has been linked with cell growth and signal transduction pathways. The PRMT1 primary transcript is alternatively spliced yielding at least three protein isoforms differing at their N-terminus. Interestingly, it has been reported that the relative prevalence of these alternatively spliced isoforms is different between normal and cancerous breast tissues, but the functional significance of this distinct expression pattern is unknown.

This project will provide a detailed biochemical characterization of PRMT1 isoforms and will initiate the study of their specific role(s) in cancer. New reagents (antibodies) will be generated and used to screen various breast tissue samples for differences relative to normal tissue. One aspect of this project will also deal with the regulation of the PRMT1 pre-mRNA alternative splicing. The results generated by this study will provide new knowledge pertinent to the biology of breast cancer. In turn, this may lead to the development of novel markers for detection of breast cancer cells within a tissue and/or the design of new therapeutic stategies.

***I am currently looking for motivated individuals (Ph. D. and Postdoctoral levels) to work on both of these projects, starting April 1st, 2008. Please contact me by email for further details.

Selected publications:

Goulet, I., Boisvenue, S., Mokas, S., Mazroui, R. and Côté, J. (2008) TDRD3, a novel Tudor domain-containing protein, localizes to cytoplasmic stress granules. Human Molecular Genetics, 17(19):3055-74.

Zhao, T.T., Cloutier, M., Lewis, S.M., Graber, T.E., Jordan, L, Goulet, I., Côté, J. and Holcik, M. (2008) hnRNP A1 regulates NFkB signaling via destabilization of cIAP1 mRNA. Cell Death and Differentiation, Accepted for publication.

Khacho, M., Mekhail, K., Pilon-Larose, K., Pause, A, Côté, J. and Lee, S. (2008) A role for the translation machinary in nuclear export. Molecular Biology of the Cell, Accepted for publication.

Tadesse, H., Deschenes-Furry, J., Boisvenue, S. and Côté, J. (2008) KH-type splicing regulatory protein interacts with survival motor neuron protein and is misregulated in spinal muscular atrophy. Human Molecular Genetics, 17(4):506-24.

Goulet, I., Gauvin, G., Boisvenue, S. and Côté, J. (2007) Alternative splicing yields prmt1 isoforms with distinct activity, substrate specificity and subcellular localization. Journal of Biological Chemistry, 282(45):33009-21.

Cheng, D., Côté, J., Shaaban, S. and Bedford, M.T. (2007) The arginine methyltransferase CARM1 regulates the coupling of transcription and mRNA processing. Molecular Cell, 25(1):71-83.

Côté, J. and Richard, S. (2005) Tudor domains bind symmetrical dimethylated arginines. Journal of Biological Chemistry, 280(31):28476-83.

Côté, J./Boisvert, F.M., Boulanger, M.C. and Richard, S. (2003) A proteomic analysis of arginine methylated protein complexes. Molecular and Cellular Proteomics, 2(12):1319- 30. Epub 2003 Oct 7.

Côté, J., Boisvert, F.-M., Boulanger, M.-C., Bedford, M.T. and Richard, S. (2003) Sam68 RNA binding protein is an in vivo substrate for protein arginine Nmethyltransferase 1. Molecular Biology of the Cell, 14(1):274-87.

Boisvert, F.-M./Côté, J., Boulanger, M.-C., Cléroux, P., Bachand, F., Autexier, C. and Richard, S. (2002) Symmetrical dimethylarginine methylation is required for the localization of SMN in Cajal bodies and pre-mRNA splicing. Journal of Cell Biology, 159(6):957-69.

Bachand, F., Boisvert, F.-M., Côté, J., Richard, S. and Autexier, C. (2002) The Product of the Survival of Motor Neuron (SMN) Gene is a Human Telomerase-Associated Protein. Molecular Biology of the Cell, 13(9): 3192-202.

Espejo A., Côté, J., Bednarek A., Richard S., Bedford M.T. (2002) A protein-domain microarray identifies novel protein-protein interactions. Biochemical Journal. 367(Pt 3):697-702.

Chen T./Côté, J., Carvajal H.V., Richard S. (2001) Identification of Sam68 arginine glycine-rich sequences capable of conferring nonspecific RNA binding to the GSG domain. Journal of Biological Chemistry. 276(33):30803-11.

Côté, J., Dupuis, S. Jiang, Z.H. and Wu, J.Y. (2001) Caspase-2 pre-mRNA alternative splicing: regulation by an intronic element containing a decoy 3’ acceptor site. Proceedings of the National Academy of Science U.S.A. 98(3):938-943.

Côté, J., Dupuis, S. and Wu, J.Y. (2001) PTB binding downstream of caspase-2 alternative exon 9 represses its inclusion. Journal of. Biological Chemistry, 276(11):8535- 43.

Jiang, Z.H., Côté, J., Kwon, J.M., Goate, A.M. and Wu, J.Y. (2000) Aberrant splicing of tau pre-mRNA caused by intronic mutations associated with the inherited dementia FTDP-17. Molecular and Cellular Biology, 20(11):4036-48.