Project description
Insight into the lifecycle of transfer RNAs
Protein synthesis, one of the most fundamental processes in biology, involves delivery of amino acids to ribosomes by transfer RNAs. The stability and functionality of these molecules depend on chemical modifications, and abnormalities in the enzymes that carry out these modifications are connected to neurodevelopmental disorders. However, it remains poorly understood how these modifications govern the lifecycle of individual transfer RNAs in human cells. The goal of the ERC-funded QUALItRNA project is to investigate how transfer RNAs are produced, how cells respond to their dysfunction and how aberrant molecules are eliminated. Project findings will advance understanding of the mechanisms underlying neurodevelopmental diseases and pave the way for the design of RNA-based therapeutics.
Objective
By delivering amino acids to translating ribosomes, transfer RNAs (tRNAs) are central to protein synthesis. These small (~76 nucleotide-long) molecules have very similar three-dimensional structures, which must withstand substantial conformational changes throughout the tRNA lifecycle. To meet these demands, tRNAs are decorated by diverse chemical modifications at multiple nucleotides by highly conserved enzymes. Defects in the genes encoding these enzymes are linked to neurodevelopmental disorders. Yet, our understanding of how chemical modifications promote the biogenesis, function, and stability of individual tRNAs is limited due to technical challenges in quantifying tRNAs and the impact of their modifications on mRNA translation in human cells. We recently developed workflows to meet these challenges, enabling dissection of the tRNA lifecycle in physiologically relevant human induced pluripotent stem cell (hiPSC)-based models. Building on these advances, this proposal aims to uncover the key mechanisms orchestrating the birth, life, and destruction of human tRNAs by answering three questions: which chemical modification steps are essential for the function of individual tRNAs; how do cells sense and respond to defects in translation due to tRNA dysfunction, and how do cells dispose of excess or aberrant tRNAs. To achieve this, we will combine functional genomics with quantitative high-throughput approaches and biochemical assays in hiPSC-derived cells and brain organoid models. This project will significantly advance our understanding of the fundamental mechanisms governing the lifecycle of tRNAs to ensure accurate and efficient protein synthesis in pluripotent and differentiated human cells, and identify molecular triggers for neurodevelopmental disorders linked to tRNA dysfunction. Our discoveries will have implications for predicting the functional consequences of pathological mutations in tRNA-modifying genes and for designing effective RNA therapeutics.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences genetics mutation
- natural sciences biological sciences genetics nucleotides
- natural sciences biological sciences genetics RNA
- natural sciences biological sciences biochemistry biomolecules proteins enzymes
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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Topic(s)
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Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
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Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
HORIZON-ERC - HORIZON ERC Grants
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2025-COG
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1090 Wien
Austria
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