Molecular mechanisms of eukaryotic ribosome biogenesis

We aim to identify pathways that when perturbed result in the development of life-threatening cancers of the blood such as myelodysplasia and acute leukaemia. Our long term goal is to use this information to design new approaches to the treatment of these devastating cancers of the blood. Recent exciting data link the origins of inherited and acquired forms of blood cancer to defects in so-called "housekeeping" processes in our cells, specifically in the assembly of the machines (called ribosomes) that make proteins. A major focus of our work is to understand in detail how ribosomes are put together from their component parts. To do this, we are learning about the three-dimensional shape of some of the key proteins involved and trying to undersrand how these proteins work together to assemble mature ribosomes. In addition to experiments in the test tube, we are also using a range of model organisms to determine the role of specific ribosome assembly factors in living cells. The fundamental insights that we hope to obtain will not only provide a deeper understanding of the fundamental mechanisms underlying the process of ribosome assembly, but will also help improve the diagnosis and long-term outlook for patients affected by disorders of ribosome synthesis and, more generally, for patients affected by cancer.

Ribosome assembly is an essential, highly conserved process that is tightly coupled to cell growth and proliferation. However, the molecular mechanism underlying this process remains 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 that are shedding new light on this process. 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) induces 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. Novel insights into the mechanisms of ribosome assembly are not only exploitable for the design of targeted therapeutics for the ribosomopathies, but also for cancer drug discovery more generally.

This research project has been designed to have an impact beyond the academic environment. Our work will benefit many stakeholders in the rare disease community including patients, patient's representatives, health care professionals, industry, policymakers and representatives of Members States of the European Organisation for Rare Diseases (EURORDIS). There are 30 million people affected by rare disorders in the EU, and all of these patients face the same problems of lack of access to information, to diagnosis, to care, to drugs and to appropriate support. By increasing awareness of the pathophysiology of rare diseases and drawing molecular links between them, our work will help promote the extension of new policy on rare disease internationally to enhance the development of new drugs and optimise access to health care. Indeed, the Shwachman-Diamond Syndrome (SDS) Foundation in the USA is actively promoting fund-raising and sponsorship to develop new treatments for this condition based on the findings emerging from our work.
Advances in our basic understanding of bone marrow failure will benefit patients, their families, their physicians, nurses, dieticians and clinical psychologists. Greater understanding of disease pathogenesis and the consequences of disease mutations in SDS helps patients and their families come to terms with their disease. Patients will also benefit by reconfiguration of the commissioning of health care provision in the UK to National Centres of Excellence, thereby increasing the referral base, and enhancing physician expertise in managing the multidisciplinary problems with which these patients present. This will benefit Addenbrookes NHS Trust by further raising its clinical profile and bringing in more resource to treat the increased number of specialist referrals.
The work will benefit clinicians who manage patients with bone marrow failure disorders and myelodysplastic syndrome by educating them in disease pathophysiology. They will pass the new insights on to their patients and colleagues. By elucidating the molecular basis of rare diseases, new links will be established between clinicians and basic scientists working in previously diverse fields.
The research will enhance the training and education of students and clinical fellows.
The general public will benefit from dissemination of our research findings as they will appreciate that advances in societal health and well being are the product of a culture that supports a strong science base and will further support investment in research.
Schoolchildren will benefit from the research by understanding more about science and its value. As a well-supported and successful science lab, we are better able to communicate our exciting ideas and to stimulate schoolchildren to consider research careers.