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Replication and post-replication signalling pathways Regulating R-loop-associated Telomere instability in human cells

Descrizione del progetto

Comprendere l’instabilità dei telomeri correlati all’R-loop nelle cellule tumorali

I telomeri sono le strutture terminali dei cromosomi conosciute per il loro ruolo nel favorire l’integrità del genoma e nel prevenire danni al DNA. Nella maggior parte delle cellule, i telomeri si accorciano in ogni divisione cellulare, a meno che la telomerasi non venga riattivata o il processo di ripristino rivolto all’omologia (conosciuto come allungamento alternativo dei telomeri, ALT) non sfoci in cellule tumorali. Il progetto RTeRloop, finanziato dall’UE, sta studiando i meccanismi che regolano gli R-loop telomerici, strutture RNA-DNA che contribuiscono all’attivazione del processo di allungamento alternativo e all’instabilità dei telomeri. Il progetto individuerà i fattori molecolari centrali nel metabolismo dell’R-loop telomerico e determinerà in che modo tali strutture sono regolate nelle cellule attraverso l’impiego di diversi meccanismi di manutenzione dei telomeri. Dato che le cellule tumorali eludono la telomerasi o il processo di allungamento alternativo dei telomeri per continuare a dividersi, i risultati del progetto hanno importanti applicazioni cliniche.

Obiettivo

Telomere stability is essential to prevent tumorigenesis and cellular senescence in human cells. Telomeres are transcribed into TERRAs, which has the ability to form R-loops with the DNA template. It is known that R-loops can hamper replication fork progression leading to hyperrecombination and genome instability. Indeed, R-loops are accumulated in telomeres of cancer cells that use the Alternative Lengthening of Telomere (ALT) maintenance mechanism to gain immortalisation and in ICF syndrome cells, associated with telomere shortening and senescence.
The mammalian ATR-mediated replication stress signalling pathway and the RAD18-UBE2B ubiquitin-ligase complex involved in post-replication repair have been recently discovered as mains regulators of R-loop accumulation, suggested to act via different mechanisms. Interestingly, both pathways affect telomeres of ALT cells, where R-loops have been proposed as drivers of ALT recombination. Whether or not replication and post-replication signalling pathways have a differential role in telomeric R-loop control is not known, but it would be of key relevance to understand the role of R-loops in telomere dynamics both in normal and cancer cells. With this aim, we will investigate the molecular mechanisms that control pathological R-loop modulation at human telomeres by focussing into their accumulation during and after DNA replication and their regulation by replication and post-replication DNA damage responses. By developing new systems that allow a precise temporal control of R-loop levels and innovative single molecular approaches to detect R-loops at the replication fork, plus the use of and unbiased proteomics analysis of isolated chromatin from telomeres, I will identify new key factors and molecular mechanisms controlling telomeric R-loops in normal and cancer cells. This knowledge will help identify possible future targets in anti-cancer therapy that specifically affect cancer cells.

Coordinatore

UNIVERSIDAD DE SEVILLA
Contribution nette de l'UE
€ 160 932,48
Indirizzo
CALLE S. FERNANDO 4
41004 Sevilla
Spagna

Mostra sulla mappa

Regione
Sur Andalucía Sevilla
Tipo di attività
Higher or Secondary Education Establishments
Collegamenti
Costo totale
€ 160 932,48