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Regulation of DNA resection, DNA repair and genomic stability by cohesin in undifferentiated Caenorhabditis elegans germ cells

Project description

How do cells decide how to repair their DNA?

Eukaryotic cells have evolved different mechanisms of responding to DNA damage and repairing DNA double-strand breaks. However, many details regarding these processes are incompletely understood. The EU-funded coDNAres project aims to shed light on how cells decide to proceed with non-homologous end-joining, which is prone to errors, or the high-fidelity homologous recombination approach. Researchers will employ Caenorhabditis elegans as a model system to elucidate how cohesins – traditionally known for keeping sister chromatids together – affect chromosome segregation and DNA repair. Results will help elucidate the role of cohesins in maintaining genomic stability.

Objective

DNA double-strand breaks (DSBs) are the most hazardous type of DNA damage threatening genomic stability. Thus, eukaryotes developed different mechanisms of DNA damage response and DNA repair pathways which are highly conserved, but not fully understood. To keep a control between error-prone (Non-Homologous End-Joining, NHEJ) and high-fidelity (Homologous Recombination, HR) mechanisms of DSB repair is essential for cell fitness, mainly exerted at the level of licensing HR by the initial step of the pathway known as DNA end resection. Therefore, a full study of this step is essential to understand genetic diseases, as cancer, with a high potential to direct future therapeutic strategies.
Cohesin complexes are high conserved factors with several roles in preventing genome instability. Cohesin are a tripartite structure ring-like where only the kleisin subunit differ, the meiosis-specific Rec8 kleisin substitutes its mitotic counterpart Rad21/Scc1. It has been described roles for cohesin in chromosome segregation and DNA repair, but as short, all based in providing close proximity of sister chromatids. But little it’s known about an active function in DNA repair further tethering DNA molecules, e. g. participating in the decision of NHEJ/HR pathway, mediating early DNA resection, or targeting other repair proteins to damage sites regulating the DNA damage response, all aims of this proposal.
We will combine the expertise of the applicant in cohesin in nematodes and the host laboratory in DNA repair to shed light and compare the active contribution in DNA repair of the SCC-1- and REC-8-cohesin complexes. The use of Caenorhabditis elegans as model system will provide a portal to the study of systemic DNA damage response mechanisms in a tissue- specific way, here the mitotically proliferating undifferentiated germ cells, of great interest for the host lab.

Fields of science (EuroSciVoc)

Keywords

Programme(s)

Topic(s)

Funding Scheme

MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)

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Call for proposal

(opens in new window) H2020-MSCA-IF-2020

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Coordinator

UNIVERSIDAD DE SEVILLA
Net EU contribution
€ 160 932,48
Address
CALLE S. FERNANDO 4
41004 Sevilla
Spain
Region
Sur Andalucía Sevilla
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 160 932,48