Descrizione del progetto
Interazioni DNA-proteine: nuovi colpevoli della formazione del cancro?
Le interazioni tra DNA e proteine sono fondamentali per molte funzioni biologiche, tra cui la trascrizione e la divisione cellulare. Tuttavia, tali interazioni sono di natura transitoria e dinamica. I legami covalenti permanenti tra proteine e molecole di DNA – noti come reticolazioni DNA-proteina (DPC, DNA–protein crosslinks) – interferiscono con il ruolo fisiologico del DNA e delle proteine, determinando instabilità genomica. Il progetto DNAProteinCrosslinks, finanziato dall’UE, studierà il meccanismo di riparazione delle DPC, che è essenziale per la vitalità delle cellule e la soppressione dei tumori. Il progetto fornirà una visione fondamentale del rilevamento delle DPC e del controllo di qualità nelle cellule, offrendo allo stesso tempo una nuova prospettiva sui percorsi che causano l’instabilità genomica.
Obiettivo
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.
Campo scientifico
Parole chiave
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-STG - Starting GrantIstituzione ospitante
80539 Muenchen
Germania