Descrizione del progetto
Topologia e integrità del genoma: il ruolo delle rotture del DNA mediate da enzimi
Il genoma umano è sottoposto a un complesso processo di avvolgimento e strutturazione per adattarsi al minuscolo nucleo di ogni cellula. Gli enzimi topoisomerasi sono fondamentali per la topologia del genoma e la sua accessibilità, consentendo il taglio e la sigillatura del DNA in base alle esigenze. Gli errori nella funzione di questi enzimi possono tuttavia portare a rotture persistenti dei filamenti di DNA, compromettere l’integrità del genoma e contribuire allo sviluppo del cancro. Finanziato dal Consiglio europeo della ricerca, il progetto TOPOmics mira a esaminare in modo esaustivo le dinamiche alla base delle rotture del DNA indotte da topoisomerasi, la loro riparazione e il conseguente impatto sull’espressione e l’integrità del genoma. I ricercatori approfondiranno inoltre l’esistenza di nuovi fattori e percorsi coinvolti nella risposta cellulare a queste lesioni del DNA dotati di un potenziale valore diagnostico e terapeutico.
Obiettivo
DNA topoisomerases are conserved nuclear enzymes that regulate DNA topology by transiently cleaving and resealing the DNA molecule, fulfilling a fundamental role in virtually every aspect of chromosome metabolism. Nevertheless, erroneous or abortive topoisomerase activity can result in persistent DNA strand breaks with the enzyme covalently attached to 3’ or 5’ DNA ends by a phosphotyrosyl bond, an anomalous structure that can compromise cell survival and/or genome integrity with the consequent implications in tumourigenesis. This peculiarity of topoisomerase catalysis also underlies the anticancer efficacy of topoisomerase poisons, which inhibit the re-ligation step of the reaction inducing the formation of DNA breaks that preferentially target highly proliferating and/or repair defective tumour cells. In addition to this link with cancer therapy, defects in the repair of topoisomerase-induced DNA damage have been linked to neurological disease. Understanding the cellular response to topoisomerase-induced breaks is therefore key for important aspects of human health, with possible implications in the development of novel diagnostic, prognostic and therapeutic tools.
This project aims at acquiring a comprehensive picture of the dynamics of topoisomerase-induced DNA breaks: from their occurrence and repair to the consequences for genome expression and integrity. We rely on the development of completely novel assays to detect and isolate the different intermediates of topoisomerase-induced break repair, and which overcome major traditional limitations in the field. These tools are subsequently used to integrate the time-dependent and genome-wide distribution of the different steps and final outcomes of the process of topoisomerase-induced DNA break repair. Furthermore, we outline original proteomic and genetic screenings to identify novel factors and pathways specifically involved the cellular response to this important type of DNA lesion.
Campo scientifico
Programma(i)
Argomento(i)
Meccanismo di finanziamento
ERC-COG - Consolidator GrantIstituzione ospitante
28029 Madrid
Spagna