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

Descrizione del progetto

Come fanno le cellule a decidere come riparare il loro DNA?

Le cellule eucariotiche hanno sviluppato diversi meccanismi di risposta ai danni del DNA e di riparazione delle rotture del doppio filamento di DNA. Tuttavia, molti dettagli riguardanti questi processi sono ancora in parte incompresi. Il progetto coDNAres, finanziato dall’UE, intende far luce sul modo in cui le cellule decidono di procedere con la saldatura non omologa delle estremità, soggetta a errori, o con l’approccio di ricombinazione omologa ad alta fedeltà. I ricercatori impiegheranno il Caenorhabditis elegans come sistema modello per chiarire in che modo le coesine – tradizionalmente note perché tengono insieme i cromatidi fratelli – influenzano la segregazione dei cromosomi e la riparazione del DNA. I risultati contribuiranno a fare chiarezza sul ruolo delle coesine nel mantenimento della stabilità genomica.

Obiettivo

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.