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Chromatin function in DNA Double Strand breaks repair: Prime, repair and restore DSB Inducible via AsiSI

Project description

The role of chromatin in DNA damage repair

Double-stranded breaks (DSBs) are a type of DNA damage that involves the complete severing of both DNA strands usually as a result of ionising radiation, chemical agents, or errors during DNA replication. Cells have evolved intricate mechanisms to repair DSBs and and preserve the integrity of the genome. However, the factors determining the choice of repair pathway remains unclear, despite the apparent involvement of the chromatin environment at the site of the break. Funded by the European Research Council, the DIvA project aims to study the role of chromatin in DSB repair. Researchers will employ genomic and proteomic technologies to investigate how damaged chromosomes reorganise within the nucleus and restore the initial chromatin landscape after repair to maintain epigenome stability.

Objective

"Among the types of damage, DNA Double Strands Breaks (DSBs) are the most deleterious, as illustrated by the variety of human diseases associated with DSB repair defects. Repair of DSB into the chromatin context raises several questions that we aim to address in this proposal. Firstly, it is likely that the chromatin environment where a break occurs influences the choice of repair pathway. Since the different DSB repair mechanisms can lead to different ""scar"" on the genome, further studies are required to elucidate how chromatin structure regulates the targeting of DSB repair machineries. Secondly, DNA packaging into chromatin hinders detection and repair of DSBs and many chromatin modifications were recently identified as induced around DSBs to facilitate repair. However, a complete picture of the chromatin landscape set up at DSB, and more specifically the set of histone modifications associated with each repair pathway (""repair histone code"") is still awaited. In addition, whether and how damaged chromosomes are reorganized within the nucleus is still unknown. Finally, once repair has been completed, the initial chromatin landscape must be faithfully restored in order to maintain epigenome stability and cell fate.
Using an experimental system we recently developed (called DIvA for DSB Inducible via AsiSI), that allows the induction of multiple sequence-specific DSBs widespread across the genome, we propose to investigate these uncovered aspects of the relationship between chromatin and DSB repair. By high-throughput genomic and proteomic technologies, we will try (i) to understand the contribution of chromatin in the DSB repair pathway choice (PRIME), (ii) to describe more thoroughly the chromatin remodeling events and the spatial chromosomes reorganization, that occur concomitantly to DSB to promote adequate repair (REPAIR), and (iii) to elucidate the processes at work to restore epigenome integrity after DSB repair (RESTORE).
"

Host institution

CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS
Net EU contribution
€ 2 000 000,00
Address
RUE MICHEL ANGE 3
75794 Paris
France

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Region
Ile-de-France Ile-de-France Paris
Activity type
Research Organisations
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Total cost
€ 2 000 000,00

Beneficiaries (1)