Objectif DNA is a highly reactive molecule that is subject to deliberate, spontaneous and environmental damage. One of the most catastrophic lesions in DNA is the double-strand break (DSB), which if left unrepaired can result in cell death, infertility, genome instability and cancer. Homologous recombination (HR) is a largely error-free mechanism of DSB repair that utilizes an intact sister or homologous chromosome as a repair template. Despite considerable progress in understanding the mechanisms of HR, very little is known about how this process is regulated. My lab has made a number of seminal discoveries that have improved our understanding of how HR is regulated in mitotic and meiotic cells. In this ERC proposal, we plan to elucidate the mechanisms that control HR events in mitotic cells and regulate HR pathway choice during meiotic recombination. We will place particular emphasis on defining the roles of RTEL1 and HELQ1 in regulating HR in mitotic and meiotic cells and will determine how dysfunction of these genes contributes to tumorigenesis. Biochemistry and proteomic approaches will be employed to determine how the Fanconi anemia (FA) pathway counteracts error-prone repair by non-homologous end joining (NHEJ), thus favouring HR repair in S-phase. The use of NHEJ inhibitors as a potential treatment of FA will be tested in existing mouse models of FA. Finally, genetic screens and proteomic analysis of HR regulators will be performed in C. elegans to elucidate the mechanisms that regulate the choice between crossover and non-crossover pathways during meiotic HR. Thus, in the work proposed here, my lab will make use of multiple experimental approaches to elucidate the mechanisms for control of HR and the consequences of dysregulated HR on human disease. Champ scientifique natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomicsnatural sciencesbiological sciencesgeneticsDNAmedical and health sciencesclinical medicineoncologymedical and health sciencesclinical medicinehematologynatural sciencesbiological sciencesgeneticsheredity Programme(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Thème(s) ERC-AG-LS2 - ERC Advanced Grant - Genetics, Genomics, Bioinformatics and Systems Biology Appel à propositions ERC-2010-AdG_20100317 Voir d’autres projets de cet appel Régime de financement ERC-AG - ERC Advanced Grant Institution d’accueil THE FRANCIS CRICK INSTITUTE LIMITED Contribution de l’UE € 2 379 103,60 Adresse 1 MIDLAND ROAD NW1 1AT London Royaume-Uni Voir sur la carte Région London Inner London — West Camden and City of London Type d’activité Research Organisations Contact administratif Stéphane Maikovsky (Mr.) Chercheur principal Simon Joseph Boulton (Dr.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée Bénéficiaires (2) Trier par ordre alphabétique Trier par contribution de l’UE Tout développer Tout réduire THE FRANCIS CRICK INSTITUTE LIMITED Royaume-Uni Contribution de l’UE € 2 379 103,60 Adresse 1 MIDLAND ROAD NW1 1AT London Voir sur la carte Région London Inner London — West Camden and City of London Type d’activité Research Organisations Contact administratif Stéphane Maikovsky (Mr.) Chercheur principal Simon Joseph Boulton (Dr.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée CANCER RESEARCH UK LBG Participation terminée Royaume-Uni Contribution de l’UE Aucune donnée Adresse 2 Redman Place E20 1JQ LONDON Voir sur la carte Région London Inner London — West Camden and City of London Type d’activité Research Organisations Contact administratif Holly Elphinstone (Ms.) Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée