Our group is interested in two crucial steps for the control of gene expression. The first one is alternative splicing which is responsible for the protein diversity required for the development of higher organisms and also for many pathological dysfunctions (genetic diseases, cancer…), offering a completely original target for the development of new chemicals with therapeutic potential. The second is the selective degradation of particular messengers allowing for a fine tuning of both the level and the timed expression of some genes.
Our studies of pre-mRNA splicing are focused on how the splicing machinery manages to locate and pair 5’ and 3’ splice sites in a tissue-specific and developmentally regulated manner. We have characterized the structure and function of novel members of the serine arginine-rich (SR) protein family and determined how their activity is regulated by phosphorylation and/or by antagonistic factors. We are using Drosophila as a model system to identify target RNA sequences of these splicing factors. As a major mechanism controlling gene expression, alternative splicing constitutes a key target for alterations leading to human diseases such as thalassemia, frontotemporal dementia, amyotrophic lateral sclerosis, premature aging (progeria) disorders and spinal muscular atrophy. We are taking advantage of the unique opportunity to combine the expertise of geneticists, clinicians and molecular biologists to study the involvement of splicing in the development of rare human diseases. To achieve this goal, we have recently developed drugs that selectively target each SR protein. To understand the relationship between mRNA fate and growth factors, we have investigated the properties of a new RRM containing protein. This protein, termed G3BP, interacts with the Src homology domain (SH3) of the ras GTPase activating protein (ras-GAP) and is involved in signal transduction. G3BP is a site specific endonuclease whose activity is modulated by phosphorylation. It can therefore be anticipated that G3BP exerts an influence on the stability of specificmRNAs. Our current work aims at characterizing the function of G3BP using mice and cell lines deficient in G3BP.