Project description
Molecular mechanisms of trans-splicing: structural and functional insights
Trans-splicing is a key mRNA processing step, where exons from two pre-mRNAs merge into one, while cis-splicing rearranges exons within a single mRNA. Though cryo-electron microscopy has advanced our understanding of cis-splicing, the mechanisms of trans-splicing remain unclear. The ERC-funded TRANSPLIC project will enhance our understanding of trans-splicing by assembling trans-splicing complexes on pre-mRNA scaffolds. It will examine the unique states of trans-spliceosomes and their molecular structures, as well as their behaviour in a cellular context. Using the protist Trypanosoma brucei (Tb), which requires trans-splicing for mRNA processing, the project will integrate in vitro methods, cryo-electron microscopy, proteomics, and artificial intelligence modelling. Targeted functional assays will reveal the sequence of events leading to trans-splicing.
Objective
Trans-splicing is an essential mRNA processing step for a significant portion of living organisms. In trans-splicing, exons from two pre-mRNA precursors merge into a single mRNA, while cis-splicing rearranges exons within the mRNA. Despite recent technical advancements in cryo-electron microscopy (cryo-EM) that movie-like resolved different stages of cis-splicing, the trans-splicing mechanism is still a black box: input and output are defined, but the single steps of how the trans-spliceosome assembles and remodels to initiate the splicing cycle lie in the dark. This limitation is partially due to the absence of molecular structures resolving trans-splicing complexes. In TRANSPLIC, I will pioneer the assembly of trans-splicing complexes on pre-mRNA scaffolds to reveal the particular states unique to trans-spliceosomes. I will determine the molecular structures of trans-spliceosomes and uncover their behavior in the cellular context. Targeted functional assays will disclose the order of events leading to trans-splicing. The protist Trypanosoma brucei (Tb) will serve as an accessible model organism because it uses trans-splicing as an obligatory and abundant mRNA processing step. I will apply an ambitious approach that integrates in vitro and cell lysate-based methods, state-of-the-art cryo-EM, cryo-electron tomography, proteomics, and artificial intelligence-based computational modeling. I will complement the study through targeted functional experiments, leading to a complete understanding of the spatial-temporal resolution of trans-splicing in trypanosomes, with wider relevance to other organisms, including humans. The targeted fusion of gene sequences through trans-splicing bears potential as a molecular tool for transcriptome editing in the future.
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 biochemistry biomolecules proteins proteomics
- natural sciences physical sciences optics microscopy
- natural sciences biological sciences genetics RNA transcriptomes
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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)
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HORIZON.1.1 - European Research Council (ERC)
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(opens in new window) ERC-2024-COG
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69117 Heidelberg
Germany
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