A molecular basis of kinetoplastids SL trans splicing
Kinetoplastids are unicellular eukaryotic parasites responsible for severe human pathologies, such as sleeping sickness, Chagas disease and leishmaniasis. Kinetoplastids have diverged early during evolution and harbor many intrigu...
ver más
31/12/2029
ULIEGE
2M€
Presupuesto del proyecto: 2M€
Líder del proyecto
UNIVERSITE DE LIEGE
No se ha especificado una descripción o un objeto social para esta compañía.
TRL
4-5
Fecha límite participación
Sin fecha límite de participación.
Financiación
concedida
El organismo HORIZON EUROPE notifico la concesión del proyecto
el día 2024-10-07
¿Tienes un proyecto y buscas un partner? Gracias a nuestro motor inteligente podemos recomendarte los mejores socios y ponerte en contacto con ellos. Te lo explicamos en este video
Información proyecto TranSplice
Duración del proyecto: 62 meses
Fecha Inicio: 2024-10-07
Fecha Fin: 2029-12-31
Líder del proyecto
UNIVERSITE DE LIEGE
No se ha especificado una descripción o un objeto social para esta compañía.
TRL
4-5
Presupuesto del proyecto
2M€
Fecha límite de participación
Sin fecha límite de participación.
Descripción del proyecto
Kinetoplastids are unicellular eukaryotic parasites responsible for severe human pathologies, such as sleeping sickness, Chagas disease and leishmaniasis. Kinetoplastids have diverged early during evolution and harbor many intriguing cellular and molecular peculiarities. Among these is their remarkably streamlined nuclear genome characterized by a high gene density and significantly divergent and specialized gene expression systems. A main example of such divergence is the polycistronic transcription of all their genes producing long messenger RNA precursors (pre-mRNAs) containing tens to hundreds of coding sequences. These pre-mRNAs are dissected into monocistronic mRNAs by SL trans-splicing, a process during which a spliced leader (SL) RNA is intermolecularly fused to the 5’end of all mRNAs by the trans-spliceosome. Although this machinery is essential for gene expression, the lack of structural information and the high divergence of its RNA and protein elements have hindered a mechanistic understanding of how kinetoplastids employ SL trans-splicing to generate their entire mRNA transcriptome. Here, we will use innovative approaches to provide the structural and mechanistic basis of SL trans-splicing in kinetoplastids by using cutting-edge structural biology techniques and state-of-the-art genetic and in silico tools. By combining genome editing, purification of endogenous trans-splicing machineries, high-resolution cryo-electron microscopy, AI-based interactome approaches, and novel in vivo assays, we will reveal the mechanism of SL snRNP biogenesis, the molecular basis for SL snRNP intermolecular recognition and activation by the trans-spliceosome, and the central mechanism of trans-splicing orchestrated by the highly divergent kinetoplastids trans-spliceosome. The outcome of this research will transform our understanding of RNA trans-splicing in eukaryotes and will pave the way for developing new drugs that specifically target this unique and essential pathway.