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Conjugation of NAD-capped RNAs to proteins by ADP-ribosyltransferases to generate RNA therapeutics

Project description

RNAylated proteins as a tool for advanced RNA therapeutics

NAD-capped RNAs can bind to target proteins via the ART ModB enzyme in a process known as RNAylation. This biomolecule, the RNAylated protein, enables targeted intracellular delivery, allowing components to function synergistically. RNAylated proteins could form the foundation for engineering cellular functions and developing advanced RNA therapeutics. The ERC-funded NAD-ART project seeks to establish RNAylated proteins as a novel tool for regulating cellular processes. The project will define design principles for these proteins to enhance control over cellular functions and develop strategies for delivering RNAylated proteins into specific cell types for precise localisation. Ultimately, it will apply these principles to target the tumour suppressor protein p53, regulating it through translation, transcription, or editing.

Objective

Background: We discovered that NAD-capped RNAs can be covalently attached to specific target proteins by the phage T4 ADP-ribosyltransferase (ART) ModB, which we term RNAylation.
Scientific problem:
RNA therapy has almost limitless yet unexplored potential. Its translation into the clinics, however, requires optimal RNA delivery with high RNA stability, efficient cellular internalisation and precise target affinity.
Hypothesis: Protein-RNA interactions are ubiquitous and central in biological control. I hypothesise that conjugating a NAD-capped nucleic acid to a protein catalysed by an ART generates a novel biomolecule – the RNAylated protein – with unique functionalities. The covalently linked protein or nucleic acid can trigger a directed intracellular delivery, where both, the protein and the nucleic acid, can become functionally active. This allows targeted modulation of translation or transcription, or editing. RNAylated proteins may provide a platform to engineer the cell and represent a starting point for the creation of next generation RNA therapeutics.
Objectives:
This project aims to establish RNAylated proteins as a fundamentally novel tool to regulate cellular processes. In objective 1, we will define the design principles for RNAylated proteins, allowing to control cellular processes. In objective 2, we will develop delivery strategies to transfer RNAylated proteins in specific cell types and allow for precise cellular localisation. In objective 3, we will combine the design and delivery principles for RNAylated proteins and apply them to target the tumour suppressor protein p53 by regulating translation, transcription or by editing.
Impact: This project will develop RNAylated proteins as next generation RNA therapeutics and deepen our understanding of how a fundamental scientific discovery –the RNAylation of proteins, catalysed by the T4 ART ModB – can be translated into an application.

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(opens in new window) ERC-2023-STG

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Host institution

PHILIPPS UNIVERSITAET MARBURG
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 1 387 292,61
Address
BIEGENSTRASSE 10
35037 Marburg
Germany

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Region
Hessen Gießen Marburg-Biedenkopf
Activity type
Higher or Secondary Education Establishments
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 1 387 292,61

Beneficiaries (2)

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