Ribosome biogenesis checkpoints in growth and cell cycle : mechanisms and diseases – RiBi

Ribosome biogenesis is a fundamental metabolic process that controls cell growth and proliferation by setting the protein synthetic capacity of the cell. It is an extremely complex and energy demanding process, since in actively growing cells, more than 70% of the total gene transcription is dedicated to ribosome production. Eukaryotic ribosome biogenesis involves transcription, covalent modification and nucleolytic processing of precursor ribosomal RNA (pre-rRNAs), assembly of the maturing rRNA with more than 80 ribosomal proteins (RPs) as well as continuous nucleo-cytoplasmic transport of RPs and of nascent ribosomal subunits. Ribosome biogenesis is assisted by several hundreds of specialized proteins and RNP factors, whose function is further supported and integrated into the nuclear framework by accessory/regulatory factors. Therefore, eukaryotic cells have developed sophisticated mechanisms: i) to match ribosome biogenesis with nutrient availability and growth factor signals; ii) to coordinate RNA Pol I-, Pol II- and Pol III-dependent transcription for the production of rRNA, mRNAs encoding RPs, and RNA components of small nucleolar ribonucleoproteins (snoRNPs) iii) to control rRNA processing and ribosome assembly in the nucleolus, and RPs mRNAs translation in the cytosol. Here, we propose a multifaceted collaborative research project to understand crucial regulatory aspects of eukaryotic ribosome biogenesis and characterize checkpoints that have evolved in mammalian cells to sense and couple the execution of ribosome biogenesis to cell growth and cell cycle progression. To this end, the two research teams will combine different approaches and expertise in molecular and cell biology, signal transduction, biochemistry and mouse genetics. Special efforts will be devoted to translating this knowledge in understanding and curing human diseases in which ribosome biogenesis is altered with special emphasis on ribosomopathies and atrophy.