Crystallographic modeling of a ribosome
The ribosome is the association of two subunits, one large (above) and one small (below). It consists mainly of RNA (in red) and some small proteins represented in dark blue in the small subunit and in green / turquoise in the large subunit. Incorrect assembly or ribosome dysfunction could be the cause of a rare disease.
Project description
My project aims at understanding the molecular defects caused by mutations in a gene implicated in a novel rare disease. There is presently no name for this disease, but mutations cause a very severe phenotype (e.g. dystonia and microcephaly). This gene is required for the biogenesis of small nucleolar ribonucleoproteins that participate in the making of ribosomes, the molecular machines that synthesize proteins in all living cells. Because the mutated gene is highly conserved amongst eukaryotes, we sought to study the effects of human mutations in our favorite model system, the yeast Saccharomyces cerevisiae. To this end we generated a conditional yeast strain to specifically inactivate the endogenous gene of the yeast and replace it by the human gene (either wild-type or mutated versions). Although yeast cells expressing the human gene are viable, those that carry the various mutated forms cannot grow, indicating that all human mutations are lethal when expressed in yeast. Further analyses revealed that the biogenesis of ribosomes is altered in mutant cells: the mutations lead to an important reduction in ribosome production. We foresee that this rare disease will join the list of “ribosomopathies”, which comprise diseases caused by mutations in genes required for the biogenesis or function of ribosomes.
Research team
Name: Sophie Sleiman, M.Sc
Supervisor: Francois Dragon (UQAM)
Laureate: Doctoral scholarship 2018