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Spatial organization of DNA repair within the nucleus

Objective

Faithful repair of double stranded DNA breaks (DSBs) is essential, as they are at the origin of genome instability, chromosomal translocations and cancer. Cells repair DSBs through different pathways, which can be faithful or mutagenic, and the balance between them at a given locus must be tightly regulated to preserve genome integrity. Although, much is known about DSB repair factors, how the choice between pathways is controlled within the nuclear environment is not understood. We have shown that nuclear architecture and non-random genome organization determine the frequency of chromosomal translocations and that pathway choice is dictated by the spatial organization of DNA in the nucleus. Nevertheless, what determines which pathway is activated in response to DSBs at specific genomic locations is not understood. Furthermore, the impact of 3D-genome folding on the kinetics and efficiency of DSB repair is completely unknown.
Here we aim to understand how nuclear compartmentalization, chromatin structure and genome organization impact on the efficiency of detection, signaling and repair of DSBs. We will unravel what determines the DNA repair specificity within distinct nuclear compartments using protein tethering, promiscuous biotinylation and quantitative proteomics. We will determine how DNA repair is orchestrated at different heterochromatin structures using a CRISPR/Cas9-based system that allows, for the first time robust induction of DSBs at specific heterochromatin compartments. Finally, we will investigate the role of 3D-genome folding in the kinetics of DNA repair and pathway choice using single nucleotide resolution DSB-mapping coupled to 3D-topological maps.
This proposal has significant implications for understanding the mechanisms controlling DNA repair within the nuclear environment and will reveal the regions of the genome that are susceptible to genomic instability and help us understand why certain mutations and translocations are recurrent in cancer

Call for proposal

ERC-2015-CoG
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Host institution

THE UNIVERSITY OF SUSSEX
Address
Sussex House Falmer
BN1 9RH Brighton
United Kingdom
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 776 220,45

Beneficiaries (2)

THE UNIVERSITY OF SUSSEX
United Kingdom
EU contribution
€ 776 220,45
Address
Sussex House Falmer
BN1 9RH Brighton
Activity type
Higher or Secondary Education Establishments
CENTRE EUROPEEN DE RECHERCHE EN BIOLOGIE ET MEDECINE
France
EU contribution
€ 1 223 529,55
Address
Rue Laurent Fries 1
67404 Illkirch Graffenstaden
Activity type
Research Organisations