Project description DEENESFRITPL DNA–protein interactions: new culprits for cancer formation? Interactions between DNA and proteins are central for many biological functions including transcription and cell division. However, these interactions are transient and dynamic in nature. Permanent covalent protein linkages with DNA molecules – known as DNA–protein crosslinks (DPCs) – interfere with the physiological role of DNA and proteins and lead to genomic instability. The EU-funded DNAProteinCrosslinks project will investigate the mechanism of DPC repair, which is essential for cell viability and tumour suppression. The project will provide fundamental insight into DPC detection and quality control in cells, offering at the same time a new perspective on pathways causing genomic instability. Show the project objective Hide the project objective Objective This project aims to address the most pressing questions in the emerging field of research on DNA-protein crosslinks (DPCs) and their repair. Covalent DPCs are highly toxic DNA lesions that block virtually all chromatin processes. DPCs are induced by various exogenous and endogenous agents, but dedicated repair mechanisms were unknown. It was previously assumed that DPCs are repaired by canonical DNA repair pathways. This has changed with my recent discovery of a specific and conserved DPC repair mechanism. I established that proteases of the SPRTN family degrade the protein components of DPCs, which maintains genome stability and ensures tumour suppression. Strikingly, DPC repair by SPRTN is essential for cellular viability, which suggests that cells are constantly challenged with substantial amounts of endogenous DPCs.I hypothesize there is an entire unexplored pathway regulating protease-based DPC repair and that DPCs are key drivers of endogenous genome instability. I will employ genetic screening approaches and develop novel functional assays to systematically define the components and working principles of this novel DNA repair pathway in mammalian cells. I will determine how DPCs are detected in a chromatin context, how different repair activities are coordinated and connected to cellular processes such as replication or transcription. Moreover, I will identify the currently elusive origins of endogenous DPCs, by investigating the essential role of the SPRTN protease.My results will not only provide insights into an essential cellular quality-control mechanism but also unravel processes causing genomic instability in human cells. Importantly, many chemotherapeutics used in the clinic exert their cytotoxicity by inducing DPCs. My results will thus have imminent implications for human health and have the potential to reveal novel drug target candidates for combination anti-cancer therapy. Fields of science natural sciencesbiological sciencesgeneticsDNAnatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsnatural sciencesbiological sciencesgeneticsgenomes Keywords Genome maintenance endogenous sources of DNA damage DNA-protein crosslink repair SPRTN protease Programme(s) H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC) Main Programme Topic(s) ERC-2018-STG - ERC Starting Grant Call for proposal ERC-2018-STG See other projects for this call Funding Scheme ERC-STG - Starting Grant Host institution LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN Net EU contribution € 1 497 375,00 Address GESCHWISTER SCHOLL PLATZ 1 80539 Muenchen Germany See on map Region Bayern Oberbayern München, Kreisfreie 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 € 1 497 375,00 Beneficiaries (1) Sort alphabetically Sort by Net EU contribution Expand all Collapse all LUDWIG-MAXIMILIANS-UNIVERSITAET MUENCHEN Germany Net EU contribution € 1 497 375,00 Address GESCHWISTER SCHOLL PLATZ 1 80539 Muenchen See on map Region Bayern Oberbayern München, Kreisfreie 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 € 1 497 375,00
