Award details

Unlocking the secrets of specialised ribosomes across eukaryotes

Reference	BB/X003086/1
Principal Investigator / Supervisor	Dr Julie Aspden
Co-Investigators / Co-Supervisors	Dr Paolo Actis, Dr Antonio Calabrese, Professor Brendan Davies, Dr Juan Fontana Jordan de Urries, Professor Mary O'Connell, Dr Emma Thomson, Professor Adrian Whitehouse
Institution	University of Leeds
Department	Sch of Molecular & Cellular Biology
Funding type	Research
Value (£)	4,570,484
Status	Current
Type	Research Grant
Start date	01/09/2022
End date	31/08/2027
Duration	60 months

Abstract

Specialised ribosomes are groups of ribosomes that specifically translate a set of mRNAs and represent a new regulatory mechanism in gene expression. This concept is relatively new, and the examples currently described are in single organisms and have limited mechanistic detail. We aim to understand the detailed molecular mechanisms of specialisation and determine common features across eukaryotes. We will study ribosome specialisation from an evolutionary, functional (translational outcome) and structural perspective, using different eukaryotic model systems (yeast, Drosophila, Arabidopsis, human cells) that cover >1 billion years of evolution. We will also develop novel tools, including nanopore-based approaches to characterise specialised ribosomes in single cells. We will apply these approaches to candidates for ribosome specialisation generated from two strategies: 1) we have selected 5 examples of specialisation from our preliminary results and the literature; and 2) we will unearth additional novel candidates of ribosome specialisation through evolutionary analyses. All our results, and those from the literature, will be collated in a public website-based platform, ensuring the legacy of the project. Overall, this programme of research will allow us to unravel precisely how heterogeneity results in specialisation, and to define a 'ribosome code' applicable to all eukaryotes. In addition to changing our understanding of gene expression, our findings have the potential to impact our understanding of several human diseases. Ribosomopathies, including Diamond-Blackfan anaemia, are caused by mutations in ribosomal proteins; and it has been suggested that specialised 'oncoribosomes' might be involved in protein synthesis dysregulation in cancers. Additionally, understanding mechanisms of ribosome specialisation will enable the modulation ribosome translation in future medical, agricultural and biotechnological applications.

Summary

The expression of genes to generate proteins is the foundation of life and, therefore, the regulation of protein synthesis is critical. For all forms of life, the ribosome is the machine responsible for protein production. Until recently it was thought that ribosomes were all equal and played a passive role, simply producing proteins; but new evidence suggests that many differences exist between ribosomes, even within a single organism. These differences are now thought to enable groups of ribosomes to translate specific genes, therefore providing an unexplored regulatory layer in protein production. These different kinds of ribosomes with altered composition and targeted function are termed 'specialised ribosomes', and are the focus of our project. Although a few types of specialisation have been identified so far, we know little about the mechanism by which specialised ribosomes target specific mRNA pools. Furthermore, our current understanding of specialised ribosomes is focused on single organisms, not across all forms of life. This is a particularly challenging problem to unravel because it requires diverse expertise in a variety of specialist approaches. To tackle these issues, we will study specialised ribosomes from a group of diverse organisms and models: yeast, insects, plants, human stem cells and during viral infection. We will employ a two-pronged approach: 1) we have selected 5 types of ribosome specialisations from our preliminary results and from the literature that we will characterise in detail across all our model systems; and 2) we will unearth novel candidates of ribosome specialisation through evolutionary analyses. Each form of specialisation will be explored using 3 different approaches: evolution (what are the common features in different organisms), translation (what genes these different ribosomes translate) and structural (how the structure of specialised ribosomes enables specialisation). In addition, we will develop novel tools to understand how ribosomes regulate protein production, including using very small pores (nanopores) to study differences in ribosomes at the single ribosome level. All the data generated within this project will be integrated in a novel public platform, ensuring the legacy of the project well after the end of the grant. Overall, our programme of research will identify common patterns of ribosome specialisation, and therefore unravel the rules which explain the ways in which specialised ribosomes act across life. Given the range of approaches required to understand how specialised ribosomes work, sLoLa-level funding is required. Each of these approaches is so specialised that our project requires research staff expert in each. In addition, working in individual systems would not provide a significant leap forward in understanding. Only by finding common themes and patterns across different model systems we will be able to understand the rules which explain how specialised ribosomes regulate protein production. This project has the potential to impact understanding of several human diseases. Specifically, there is a family of diseases caused by mutations of ribosome components, ribosomopathies, for which our work may provide insight into the mechanisms of disease and potential therapeutic targets. Specialised ribosomes have also been suggested to be generated during disease e.g. cancer. Such 'onco-ribosomes' might contribute to deregulating protein synthesis in cancer. Our research programme will lead to the novel ability to modulate ribosome composition and output in future medical, agricultural, and biotechnological applications. In summary this project to dissect the regulatory mechanisms of specialised ribosomes will enable us to formulate a 'ribosome code' to explain shared mechanisms of ribosome translation regulation across life and re-write the textbooks on the central dogma of molecular biology.

Committee	Research Committee C (Genes, development and STEM approaches to biology)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	Longer and Larger Grants (LoLas) [2007-2015]
Funding Scheme	X – not Funded via a specific Funding Scheme

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