Objetivo 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. Ámbito científico natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsproteomicsnatural sciencesbiological sciencesgeneticsDNAmedical and health sciencesclinical medicineoncologymedical and health sciencesclinical medicinehematologynatural sciencesbiological sciencesgeneticsheredity Programa(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) Tema(s) ERC-AG-LS2 - ERC Advanced Grant - Genetics, Genomics, Bioinformatics and Systems Biology Convocatoria de propuestas ERC-2010-AdG_20100317 Consulte otros proyectos de esta convocatoria Régimen de financiación ERC-AG - ERC Advanced Grant Institución de acogida THE FRANCIS CRICK INSTITUTE LIMITED Aportación de la UE € 2 379 103,60 Dirección 1 MIDLAND ROAD NW1 1AT London Reino Unido Ver en el mapa Región London Inner London — West Camden and City of London Tipo de actividad Research Organisations Contacto administrativo Stéphane Maikovsky (Mr.) Investigador principal Simon Joseph Boulton (Dr.) Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Coste total Sin datos Beneficiarios (2) Ordenar alfabéticamente Ordenar por aportación de la UE Ampliar todo Contraer todo THE FRANCIS CRICK INSTITUTE LIMITED Reino Unido Aportación de la UE € 2 379 103,60 Dirección 1 MIDLAND ROAD NW1 1AT London Ver en el mapa Región London Inner London — West Camden and City of London Tipo de actividad Research Organisations Contacto administrativo Stéphane Maikovsky (Mr.) Investigador principal Simon Joseph Boulton (Dr.) Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Coste total Sin datos CANCER RESEARCH UK LBG La participación finalizó Reino Unido Aportación de la UE Sin datos Dirección 2 Redman Place E20 1JQ LONDON Ver en el mapa Región London Inner London — West Camden and City of London Tipo de actividad Research Organisations Contacto administrativo Holly Elphinstone (Ms.) Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Coste total Sin datos