Ribosomes—the protein-making factories inside every cell—malfunction in certain inherited diseases that dramatically raise the risk of childhood leukaemia and other cancers. The problem is that scientists do not fully understand how ribosomes assemble themselves in the final stages. This gap matters because cancer cells are addicted to protein synthesis, making ribosome assembly a promising target for new drugs. In Shwachman-Diamond syndrome, a single faulty protein disrupts the release of a factor called eIF6 from the large ribosomal subunit, but the precise molecular choreography remains unknown. This project will use cutting-edge cryo-electron microscopy to map the atomic structures of ribosome assembly intermediates at better than 2 Å resolution—a technical feat that has so far been out of reach. By combining structural biology with molecular dynamics simulations, biochemistry, and human genetics, the researchers aim to reveal how the cell checks ribosome quality before allowing it to start making proteins. If successful, the work could open routes to treatments for ribosomopathies and, more broadly, identify vulnerabilities in cancer cells that might be exploited with new drugs. This is fundamental science: it seeks a mechanistic understanding of a core cellular process, with no guarantee of immediate clinical application. But past discoveries in ribosome biology have already shaped how we understand and treat disease.
View original technical description
Ribosome assembly is a highly conserved process that is essential for cellular protein synthesis. Better understanding of this fundamental cellular process is important as the “addiction” of cancer cells to protein synthesis is stimulating efforts to exploit this as a druggable vulnerability. In addition, ribosomopathies are a devastating group of diseases caused by germline ribosome deficiency that substantially increase the risk of cancer in children and young adults (up to 40% in the 4th decade of life). In prior MRC-supported work, my lab determined that the SBDS protein that is deficient in the inherited leukaemia predisposition disorder Shwachman-Diamond syndrome (SDS), is crucial for maturation of the large ribosomal subunit. We defined SDS as a ribosomopathy that is caused by defective release of the anti-association factor eIF6 from the nascent large ribosomal subunit. However, the molecular mechanisms underlying this process remain incompletely understood. Our goal is to elucidate the basic molecular mechanisms of late cytoplasmic ribosome assembly to facilitate the development of novel treatments for ribosomopathies and cancer more broadly. A major barrier to progress has the lack of detailed structures of native pre-60S ribosome assembly intermediates, which are highly dynamic and often transient. We will fill this knowledge gap by leveraging ground-breaking technology developed in our lab to resolve ribosome structures to better than 2 Å using single particle cryo-electron microscopy (cryo-EM). This project demands a multidisciplinary approach, integrating structural studies with detailed molecular dynamics, biochemical, biophysical and genetic approaches. The timeliness and feasibility of this programme is supported by our published work and strong preliminary data. Our central hypothesis is that a coordinated and dynamic network of protein-RNA interactions functionally proofreads ribosome quality during nascent 60S subunit assembly. We will address this hypothesis with the following specific aims: Determine how GTPase activation is coupled to structural rearrangements during 60S subunit maturation Determine mechanisms regulating entry of the nascent ribosomal subunit into active translation Determine mechanisms regulating eIF6 function Our discovery based Programme will provide a step change in understanding the biological mechanisms involved in ribosome assembly, build new capabilities in the field and help improve human health. The work addresses a clear unmet need to improve the quality of life and survival of patients affected by ribosomopathies. Furthermore, the results may be exploitable for cancer drug discovery. The programme fits within the MRC strategy of driving an integrated understanding of human disease, securing better health, ageing and wellbeing and is aligned within the Government’s Life Sciences Vision. The work involves a unique combination of structural biology, molecular dynamics simulations, biochemistry, cell biology and human genetics to make discovery-based basic scientific advances and supports the breadth and diversity of skilled people needed for the future research and development workforce.
Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.
Is something wrong? Let us know