Project description
DNA damage response and protein degradation
The EU-funded ExploDProteins project aims to use small molecules to degrade proteins around sites of DNA damage using the damage itself as a targeting signal. The approach will create new possibilities to study DNA damage and will also offer translational opportunities in cancer treatment. Cancer cells are often acutely sensitive to DNA damage because they have some faulty DNA damage response (DDR) pathways, making them highly dependent on their remaining DNA repair systems. E3 ligases are modular multi-protein complexes that modify and, in some cases, destabilise cellular proteins by catalysing the formation of polyubiquitin chains on the substrates, targeting them for proteasomal degradation. The project will reprogramme E3 ligases to selectively kill cancer cells by modulating DDR pathways.
Objective
Here I propose to use small molecules to degrade proteins specifically around sites of DNA damage by using the damage itself as a homing signal. The approach will create new ways to study DNA damage, but will also offer translational possibilities in cancer. Cancer cells are often acutely sensitive to DNA damage because they have one or more faulty DNA damage response (DDR) pathways – a feature that makes them highly dependent on their remaining DNA repair systems. We will pioneer two novel and related chemical approaches for selectively killing cancer cells by modulating DDR pathways with bifunctional DNA damaging molecules. We will do this by reprogramming E3 ligases. E3 ligases are modular multi-protein complexes that destabilize cellular proteins by catalysing the formation of polyubiquitin chains on its substrates, which serve as a signal for proteasomal degradation. A recent revolutionary advance in chemical biology is to use small molecules to reprogram the protein degradation specificity of E3 ligases. By degrading proteins instead of inhibiting them, these small molecules achieve levels of functional modulation typically only possible with genetic techniques. We are inspired by this new protein degradation technology, but will take it in a new direction. Chemical damage of DNA recruits E3 ligases as well as critical DDR proteins in preparation for DNA repair. We will invent a new generation of small molecule protein degradation catalysts by repurposing these natural responses to DNA damage.
We will accomplish our goal with three aims:
Aim 1: Use DNA damage as a homing signal for induced protein degradation
Aim 2: Use direct repair of DNA damage by the repair protein MGMT to promote the degradation of other proteins
Aim 3: Promote pleiotropic protein degradation by recruiting broadly acting E3 ligases to sites of DNA damage
I propose an ambitious project that will create conceptually novel ways to study the DDR and potentially build new medicines.
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.
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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)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC)
MAIN PROGRAMME
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Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
ERC-COG - Consolidator Grant
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) ERC-2019-COG
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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.
4051 Basel
Switzerland
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.