Stéphane Richard, Ph.D., Associate Professor
William Dawson Scholar
Departments of Medicine and Oncology, McGill University

  
My research focuses on elucidating the molecular signaling mechanisms in normal and diseased cells. Our research has implications for aging, cancer, multiple sclerosis, osteoporosis, and obesity.

Projects :
1) Define the role of the novel post-translational modification, arginine methylation, in genomic instability. Implications for aging and tumorigenesis.
The primary sequence of a protein is dictated by the genetic code and functional diversity can then be achieved by the lamination of different post-translational modifications. Phosphorylation remains by far the most studied and understood post-translational modification with the identification of large families of kinases, phosphatases and proteins containing phosphoprotein-interacting modules. Arginine was shown to contain methyl groups as early as 1967, but the distinguished status of arginine methylation is only now ascending into prominence. Arginine is a positively charged amino acid known to mediate hydrogen bonding and amino-aromatic interactions. The nitrogens of arginine within polypeptides can be post-translationally modified to contain methyl groups, a process termed arginine methylation.The role of protein methylation in the DNA response pathway is largely unexplored. The identification of the MRE11-RAD50-NBS1 double strand break repair protein complex with ASYM25, an aDMA specific antibody, suggested that at least one of its components is arginine methylation. Indeed, MRE11 harbors a signature GAR motif known to be the target of PRMTs and it remains to be determined whether methylation will regulate its exonuclease activity, protein localization and/or complex assembly. 53BP1 is another central mediator of the DNA damage checkpoint and it also harbors a GAR motif, which has been shown to interact with its Tudor domains. Further studies are required to determine whether arginine methylation will regulate checkpoint control during DNA damage and whether faulty methylation leads to genomic instability.

2) Define the role of QUAKING proteins in oligodendrocyte myelination. Implications for multiple sclerosis.
Axons are covered with a multi-layered insulating membrane called myelin.
Myelin is a complex mixture of myelin-specific lipids and membrane associated proteins that are layered into a compact sheath. Myelin basic proteins, myelin associated glycoproteins, and proteolipid proteins are the predominant proteins found in myelin and are thought to play important roles in compaction and the structure of myelin. Demyelination of the central nervous system axons results in the multiple sclerosis, a neurological disease where symptoms vary and range from numbness, tingling sensations to paralysis, blindness and seizures. Several mutations have been identified in mice that result in dysmyelination. The genetic defect for one such mouse named 'quaking' has been identified and does not involve a component of myelin. Research using the quaking mice imply that the quaking protein (QKI) is a regulator of myelination and/or required for the proper maturation/survival of themyelin producing cells.The research in my laboratory focuses on understanding the role of QKI in the myelin producing cell, the oligodendrocytes. This knowledge should increase our understanding of myelination and may provide new strategies for the development of drugs for treatment of multiple sclerosis.

3) Define the role of RNA bindig proteins in cell growth, cell fate determination, tumorigenesis and metabolism. Implications for glioblastomas, breast cancer, osteoporosis and obesity.
Osteoporosis is a debilitating bone disease that is characterized by reduced bone mass and micro-architectural damage, which result in increased bone fragility and susceptibility to fracture. Peak bone mass, which is achieved by the age of 30 in men and women, has been identified as a major determinant of resistance or susceptibility to osteoporosis. We generate mice deficient for the Sam68 RNA binding protein, a protein of unknown physiological function. The mice develop normally and are protected against aging bone loss. Aging bone loss, has long been associated with an increase in marrow adipocytes, as osteoblasts and adipocytes are derived from a common mesenchymal precursor cell present in bone marrow. We found that Sam68 regulates the differentiation of the mesenchymal stem cell such that osteoblasts continue to be generated with aging leading to a preservation of peak bone mass. This study identifies a physiological role for Sam68 as a modulator of mesenchymal stem cell and bone metabolism. Further, the data identify Sam68 as a therapeutic target for treating aging bone loss and adipogenesis. We are currently studying the role of Sam68 and other family members in tumorigenesis.

SOME RECENT PUBLICATIONS