Alternative 18S rRNA 3' processing pathways in human ribosome biogenesis

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Life depends on the ability of an organism to react to changing environments and stresses by controlling the synthesis of complex macromolecules. Normal cell growth requires the production of ribosomes, the essential RNA-protein machinery that makes all cellular proteins. Ribosome assembly, a complicated process involving hundreds of biogenesis factors, is the major consumer of cellular energy and therefore tightly controlled. In cancer cells, ribosome production is upregulated to promote cell proliferation. Many cellular stresses and 20 genetic diseases ("ribosomopathies") result in a block or defect in ribosome production. Surprisingly, ribosomopathy patients are often pre-disposed to cancer and some cancers have also recently been linked to defective ribosome production. In humans, ribosome assembly controls the tumour suppressor p53, the "guardian of the genome". Through cellular signaling, p53 ensures appropriate cellular responses to stress conditions, and can even induce cell death if individual cells are detrimental to the whole organism. Indeed, p53 levels are elevated in many ribosomopathies and p53 is essential for many of the clinical features observed in these diseases.Here, we propose to study the impact of disease-associated mutations in key biogenesis factors on human ribosome production, p53 and cellular survival. Our internationally recognised expertise in ribosome biogenesis, RNA processing and cellular signaling, together with our strong preliminary data, mean that we are ideally placed to successfully carry out this project.Due to the high degree of evolutionary conservation in the ribosome production machinery, it was long assumed that ribosome production is the same in humans as it is in yeast, the main model organism used to study this process. However, we have now shown that the process of human ribosome production is significantly more complicated, and fundamentally different to that used in yeast. Surprisingly, human cells also retain the machinery needed for a "yeast-like" mechanism, however, this pathway is rarely used in humans and it is unclear what role it plays. Increasing our fundamental knowledge of human ribosome production is therefore of paramount importance for elucidating the basis of several human diseases and the development of potential treatments.WE WILL THEREFORE ADDRESS TWO KEY QUESTIONS:1) Do disease-associated mutations in key ribosomal RNA maturation factors cause defects or changes in ribosome production?2) Why do human cells use a specialised ribosomal RNA maturation pathway when they also have the machinery to employ a "yeast-like" mechanism?We will use a powerful combination of molecular tools and state-of-the-art technologies to reveal the mechanism(s) of human ribosome production and understand how this is altered in disease. This project will include determining the impact of disease-associated mutations on human ribosome production and p53-dependent cellular signaling, as well as using novel approaches to understand why human cells use a specialised ribosome production pathway. Intriguingly, our preliminary data also suggest that some cancer cells might depend on the minor, "yeast-like" mechanism. This raises the exciting possibility that this pathway could be targeted for the development of anti-cancer drugs in the future.