The production of fully functional ribosomes is vital for every cell, with failure causing human diseases called ribosomopathies. Eukaryotic ribosome assembly is catalyzed by ~200 assembly factors that guarantee efficient and accurate production of ribosomal subunits along a temporally and spatially ordered pathway. About one third of these factors are utilized in the formation of the earliest biogenesis intermediate, termed 90S pre-ribosome or small subunit processome. Recent insight into the 90S structure from a eukaryotic thermophile, Chaetomium thermophilum, has provided a first spatial impression on this most sophisticated process, which includes co-transcriptional RNA folding and processing, and incorporation of ribosomal proteins. Our key discovery was that the nascent ribosomal RNA, which if linear would form a long thread, is co-transcriptionally mounted into a mold formed by a highly interconnected RNA-protein scaffold on the 90S pre-ribosome. This finding raises a novel concept in RNA biology that nascent RNA folds and matures in a protected environment, which is reminiscent of protein folding that can also occur in folding chambers. I plan to challenge the idea that the 90S particle indeed encapsulates the RNA transiently, in order to protect it from unproductive interactions, allowing stepwise folding and maturation in a cascade of interdependent reactions and the involvement of energy-consuming enzymes. The groundbreaking aim of this proposal is to decipher how these processes occur in an encapsulated environment, using C. thermophilum as a model organism. This high-risk project will depend on the successful establishment of novel assays that recapitulate eukaryotic ribosome assembly in vitro, exploiting the thermostable nature of the 90S pre-ribosome. Mechanistic insight into ribosome biogenesis will lead to a better understanding of how this multifaceted process is linked to other key cellular pathways and development of diseases including cancer.
Fields of science
Call for proposalSee other projects for this call
Funding SchemeERC-ADG - Advanced Grant
See on map
See on map