Project description DEENESFRITPL 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. Show the project objective Hide the project objective 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 degradationAim 2: Use direct repair of DNA damage by the repair protein MGMT to promote the degradation of other proteinsAim 3: Promote pleiotropic protein degradation by recruiting broadly acting E3 ligases to sites of DNA damageI propose an ambitious project that will create conceptually novel ways to study the DDR and potentially build new medicines. Fields of science natural sciencesbiological sciencesgeneticsDNAnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsmedical and health sciencesclinical medicineoncologynatural scienceschemical sciencescatalysis Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2019-COG - ERC Consolidator Grant Call for proposal ERC-2019-COG See other projects for this call Funding Scheme ERC-COG - Consolidator Grant Host institution UNIVERSITAT BASEL Net EU contribution € 1 940 756,00 Address PETERSPLATZ 1 4051 Basel Switzerland See on map Region Schweiz/Suisse/Svizzera Nordwestschweiz Basel-Stadt Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 940 756,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all UNIVERSITAT BASEL Switzerland Net EU contribution € 1 940 756,00 Address PETERSPLATZ 1 4051 Basel See on map Region Schweiz/Suisse/Svizzera Nordwestschweiz Basel-Stadt Activity type Higher or Secondary Education Establishments Links Contact the organisation Opens in new window Website Opens in new window Participation in EU R&I programmes Opens in new window HORIZON collaboration network Opens in new window Total cost € 1 940 756,00
