Ziel
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.
Wissenschaftliches Gebiet (EuroSciVoc)
CORDIS klassifiziert Projekte mit EuroSciVoc, einer mehrsprachigen Taxonomie der Wissenschaftsbereiche, durch einen halbautomatischen Prozess, der auf Verfahren der Verarbeitung natürlicher Sprache beruht.
CORDIS klassifiziert Projekte mit EuroSciVoc, einer mehrsprachigen Taxonomie der Wissenschaftsbereiche, durch einen halbautomatischen Prozess, der auf Verfahren der Verarbeitung natürlicher Sprache beruht.
- NaturwissenschaftenBiowissenschaftenBiochemieBiomoleküleProteineProteomik
- NaturwissenschaftenNaturwissenschaftenOptikMikroskopie
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Schlüsselbegriffe
Programm/Programme
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thema/Themen
Finanzierungsplan
HORIZON-ERC - HORIZON ERC GrantsGastgebende Einrichtung
69117 Heidelberg
Deutschland