Descripción del proyecto
Interacciones ADN-proteína: ¿son los nuevos culpables de la formación del cáncer?
Las interacciones entre el ADN y las proteínas son fundamentales para muchas funciones biológicas, como la transcripción y la división celular. Sin embargo, estas interacciones son de transitorias y dinámicas por naturaleza. Los enlaces covalentes permanentes de las proteínas con las moléculas de ADN —denominados «reticulaciones de ADN y proteínas» (DPC, por sus siglas en inglés)— interfieren en la función fisiológica del ADN y las proteínas y conducen a una inestabilidad genómica. El equipo del proyecto DNAProteinCrosslinks, financiado con fondos europeos, investigará el mecanismo de reparación de la DPC, que es esencial para garantizar la viabilidad celular y la supresión de tumores. El equipo del proyecto proporcionará información esencial sobre la detección y el control de calidad de la DPC en las células y, al mismo tiempo, ofrecerá una nueva perspectiva sobre las vías que causan la inestabilidad genómica.
Objetivo
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.
Ámbito científico
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Programa(s)
Régimen de financiación
ERC-STG - Starting GrantInstitución de acogida
80539 Muenchen
Alemania