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Ribosomopathies

Project description

My research program focuses on ribosome biogenesis and nucleolar function. The nucleolus is a specialized compartment of the cell nucleus: it is the site of ribosome production, and it is often seen as a “ribosome factory”. However, this view has changed over the last 20 years because other functions have been discovered for the nucleolus, including roles in cell-cycle control, aging and viral replication. Nevertheless, the principal function of the nucleolus remains ribosome biogenesis. This biological process is very complex and finely tuned: more than 200 nucleolar factors (proteins) and as many small non-coding RNAs participate in the making of each ribosome. In a rapidly growing cell, nearly 4000 ribosomes are produced every minute. It is therefore crucial to properly control the entire process…
A number of genetic diseases result from mutations in factors involved in the production of ribosomes, or even ribosomes constituents themselves (e.g. Diamond-Blackfan anemia caused by mutations in ribosomal proteins). Diseases affecting ribosome structure and/or function are now grouped under the heading of “ribosomopathies”. These are rare diseases, and the molecular mechanisms underlying the “manufacturing defects” of ribosomes are poorly understood. In my laboratory we use the yeast Saccharomyces cerevisiae as a model to study the early stages of ribosome formation. Using the powerful tools of yeast molecular genetics, we have contributed to the advancement of knowledge on key nucleolar factors such as Dbp4/DDX10, Kre33/NAT10 and Shq1/SHQ1 (yeast/human). Our current work on Kre33 and Shq1 is directly related to rare diseases. Indeed, the RNA acetyltransferase NAT10 is linked to Hutchinson-Gilford progeria syndrome, an accelerated aging syndrome for which there is no treatment (incidence 1/4,000,000). Mutations in the gene SHQ1 have recently been identified in two Canadian siblings; these children have severe developmental problems (dystonia, microcephaly, intellectual disability), and we have been contacted by the Canadian “Rare Diseases: Models and Mechanisms” Network to undertake studies in yeast in order to elucidate the molecular mechanisms that are altered by mutations in SHQ1. Later we learned that an Australian patient presented the same phenotype as the two Canadian sisters and had similar mutations in SHQ1. Our work in yeast revealed that the different mutations in SHQ1 cause a significant ribosome manufacturing defect. We are convinced that this novel rare disease will soon be recognized as a ribosomopathy.

Laboratory

Laboratory of Pr François Dragon (UQAM)
Laureate: 2019 teaching allowance

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