Projektbeschreibung
Die R-Loop-assoziierte Telomerinstabilität in Krebszellen verstehen
Telomere sind die Endstrukturen der Chromosomen, die dafür bekannt sind, dass sie die Genomintegrität bewahren und vor DNA-Schäden schützen. In den meisten Zellen werden die Telomere bei jeder Zellteilung kürzer – es sei denn, die Telomerase wird reaktiviert oder der homologiegeleitete Reparaturprozess, die sogenannte alternative Telomerverlängerung (Alternative Lengthening of Telomeres, ALT), findet in den Krebszellen statt. Das EU-finanzierte Projekt RTeRloop erforscht nun die Mechanismen, die telomere R-Loops regulieren. Diese RNA-DNA-Strukturen tragen zur ALT-Aktivierung und zur Telomerinstabilität bei. Das Projekt wird die wichtigsten molekularen Beteiligten am telomeren R-Loop-Stoffwechsel bestimmen und ermitteln, wie diese Strukturen in Zellen reguliert werden, die verschiedene Telomererhaltungsmechanismen anwenden. In Anbetracht der Tatsache, dass Krebszellen ALT-Zellen oder Telomerase entführen, um sich weiter zu teilen, werden die Projektergebnisse wichtige klinische Anwendungen finden.
Ziel
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.
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MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Koordinator
41004 Sevilla
Spanien