Objectif Homologous recombination (HR) is an essential DNA repair mechanism and defects in different HR factors are linked with disease and cancer pre-disposition. The RAD51 recombinase plays a central role in HR, forming nucleoprotein filaments at sites of DNA damage and promoting homologous pairing and DNA strand exchange. RAD51 filament formation is mediated by the BRCA2 tumour suppressor, mutations in which lead to a high incidence of developing breast cancer. BRCA2 interacts with other HR factors, such as PALB2 and members of the RAD51 paralog family. Many of these proteins also function as tumour suppressors. The host laboratory has purified full-length BRCA2 protein and shown that it facilitates RAD51-mediated HR by acting as a molecular chaperone for RAD51 filament formation. This offers a unique position to extend our understanding of pre-recombinational protein assembly by inclusion of additional critical HR factors, and answer the important question how PALB2 and the RAD51 paralogs coordinate their activities with BRCA2 to promote the assembly of RAD51 filaments. To achieve this, I propose to:i) Characterize the biochemical and structural properties of RAD51 paralog complexes ii) Define the interplay between BRCA2, PALB2, and the RAD51 paralogs in forming pre-recombination complexes for RAD51 assembly, using biochemical approaches and electron microscopic visualisation.Given the importance of HR and its role in tumour avoidance, I anticipate our results to provide significant new insights into the molecular mechanisms underlying genome instability. Also, they may uncover novel targets for therapeutic intervention for breast cancer. Together, the proposed research will not only substantially advance knowledge of DNA repair but will also provide me with invaluable training in biochemistry, electron microscopy and project management in a world-class research environment. As such, it forms the perfect platform from which to launch my independent research career. Champ scientifique natural sciencesbiological sciencesbiochemistrynatural sciencesbiological sciencesgeneticsDNAmedical and health sciencesclinical medicineoncologybreast cancernatural sciencesbiological sciencesmolecular biology Mots‑clés DNA repair Homologous recombination RAD51 paralogs BRCA2-RAD51-PALB2 Cancer Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Thème(s) MSCA-IF-2014-EF - Marie Skłodowska-Curie Individual Fellowships (IF-EF) Appel à propositions H2020-MSCA-IF-2014 Voir d’autres projets de cet appel Régime de financement MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF) Coordinateur THE FRANCIS CRICK INSTITUTE LIMITED Contribution nette de l'UE € 183 454,80 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 Liens Contacter l’organisation Opens in new window Site web Opens in new window Participation aux programmes de R&I de l'UE Opens in new window Réseau de collaboration HORIZON Opens in new window Coût total € 183 454,80 Participants (1) Trier par ordre alphabétique Trier par contribution nette de l'UE Tout développer Tout réduire CANCER RESEARCH UK LBG Participation terminée Royaume-Uni Contribution nette de l'UE € 0,00 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 Liens Contacter l’organisation Opens in new window Site web Opens in new window Participation aux programmes de R&I de l'UE Opens in new window Réseau de collaboration HORIZON Opens in new window Coût total Aucune donnée