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Tracking the movement and dynamics of Holliday junctions

Project description

Tracking DNA damage repair

DNA damage repair is paramount to maintaining genomic integrity and preventing cancer. Homologous recombination (HR) ensures the repair of double strand breaks in DNA through key intermediates known as Holliday junctions (HJ). The EU-funded HollidayTrack project will develop molecular tools for detecting and determining the dynamic properties of HJ structures in cells. It will address the impact of local chromatin structure on HJ migration and resolution as well as the role of HJs in telomere biology. Collectively, the project's results will advance our knowledge on the patterns and distributions of HJ formation and migration in different cancer cell types.

Objective

omologous recombination (HR) is a DNA repair pathway that plays a central role in the maintenance of genomic stability and cancer prevention. In the late stages of HR, recombination intermediates (Holliday junctions, HJs) need to be resolved to allow proper chromosome segregation. Whilst HJ processing reactions have been well characterised in vitro, there is limited knowledge of the dynamic properties of these structures within a cellular context. To explore the biological properties of HJs in vivo, I will use site-specific DNA cleavage and ChIP-sequencing techniques to reveal the distance of HJ migration from the site where HR is initiated. The ability of HJs to branch migrate spontaneously or be driven by potential HJ translocases will be determined using RAD54, BLM, WRN, RECQ1, RECQ5 and FANCM deficient cells. To enable these studies, my first challenge will be to develop a molecular tool that specifically detects HJs in vivo, that can be used to monitor the appearance and kinetics of HJs after DNA double strand break formation. The specific DNA break sites and corresponding HJ migration will be determined with respect to the dynamic chromosome domain architecture and organisation within human cells, which will provide valuable insights into the impact of local chromatin structure on HJ migration and resolution. Additionally, the newly developed HJ-specific tools may be applied to ask a wide range of questions relating to the role of HJs in telomere biology and replication fork reversal or to study patterns and distributions of HJ formation and migration in different cancer cell types.

Coordinator

THE FRANCIS CRICK INSTITUTE LIMITED
Net EU contribution
€ 212 933,76
Address
1 MIDLAND ROAD
NW1 1AT London
United Kingdom

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Region
London Inner London — West Camden and City of London
Activity type
Research Organisations
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Total cost
€ 212 933,76