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Multivalent interactions driving RNP dynamics in development and disease

Project description

Ribonucleoproteins remodelling in development and disease

A ribonucleoprotein (RNP) is a complex of ribonucleic acid and RNA-binding protein. These complexes play an integral part in important biological functions including DNA replication, gene expression regulation and RNA metabolism. Some mutations causing cancer or neurodegenerative diseases (such as amyotrophic lateral sclerosis) occur in RNA-binding proteins. These mutations are concentrated in the intrinsically disordered regions of the proteins which lack a well-defined 3D structure but play important roles in protein regulation, including RNP assembly and disassembly. The EU-funded RNPdynamics project will build a framework of experimental and computational methods to study the mechanisms of RNP remodelling, and to explore how such RNP dynamics contribute to cellular transitions in development and disease.

Objective

Ribonucleoprotein complexes (RNPs) play many key regulatory roles in development. Moreover, mutations causing cancer or neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), often occur in RNA-binding proteins (RBPs). These mutations are concentrated in the intrinsically disordered regions (IDRs), which play a central role in the control of RNP assembly and disassembly. RNP dynamics is often driven by multivalent interactions that are mediated by multiple elements within IDRs of RBPs, which can condense the RNP such that it separates from the surrounding liquid through the phenomenon of liquid-liquid phase separation. Transcriptomic insights into the physiological functions of such multivalent RNP assembly are needed to understand their regulation, or deregulation through disease-causing mutations. Here, we will build a framework of experimental and computational methods to study the mechanisms by which the dynamic multivalent interactions drive RNP remodelling, and how such RNP dynamics contributes to cellular transitions in development and disease. The first objective will be to identify the functions of specific RBPs in cell-state transitions during neuronal differentiation, and the mechanisms of IDR-mediated multivalent interactions in these functions. The next objective will be to establish new tools to manipulate RNP assembly through multivalent RNA binding sites and IDRs. Finally, the new insights and tools will be integrated with the goal to fine-tune the RNP assembly of ALS-mutant RBPs, and thereby ameliorate their toxicity.

Host institution

KEMIJSKI INSTITUT
Net EU contribution
€ 1 827 418,25
Address
HAJDRIHOVA 19
1000 Ljubljana
Slovenia

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Region
Slovenija Zahodna Slovenija Osrednjeslovenska
Activity type
Research Organisations
Links
Total cost
€ 1 827 418,25

Beneficiaries (4)