Molecular mechanisms of eukaryotic ribosome biogenesis

Human leukaemias are a significant cause of morbidity and mortality in children and adults. However, we have little understanding of the molecular basis of the multistep progression to leukaemia. A major goal of our studies is to identify and characterise the function of new molecules that participate in the development of these cancers of the blood. We further aim to determine the three-dimensional shape of the molecules involved in order to facilitate the development of novel targeted approaches to therapy.

Ribosome assembly is an essential, highly conserved process that is tightly coupled to cell growth and proliferation. However, the molecular mechanisms underlying this process remain poorly understood. Excitingly, a new class of cancer predisposition syndromes collectively called the “ribosomopathies” has recently emerged that harbour mutations in components of the ribosome assembly pathway. In particular, we have discovered that the SBDS protein that is deficient in the leukaemia predisposition disorder Shwachman-Diamond syndrome is required for maturation of the large ribosomal subunit. SBDS controls the translational activation of ribosomes by catalysing dissociation of the anti-association factor eIF6 from nascent 60S subunits, but the precise mechanism remains unclear. We propose a model in which GTP-dependent conformational change in elongation factor-like 1 (EFL1) triggers an inter-domain rotation in SBDS that directly or indirectly triggers eIF6 release. We aim to test this hypothesis at the molecular level by combining the latest advances in single-particle cryo-electron microscopy and NMR spectroscopy with X-ray crystallography, biochemistry and innovative genetic platforms. We will test the hypothesis that eIF6 release is a prerequisite for eviction of additional assembly factors whose specific role in ribosome assembly we will determine. Finally, we will apply state-of-the-art genetic approaches to identify additional components of the pathway. Novel insights into the mechanisms of ribosome assembly are exploitable not only for the design of targeted therapeutics for the ribosomopathies, but also for cancer drug discovery more generally.
To facilitate translation of this work to direct clinical care, we have initiated collaborations with paediatric haematologists in the UK and in Europe. We will participate in tissue banking to facilitate prospective studies through the Haematology Department at Addenbrookes Hospital in accordance with National and Local ethical guidelines.