Description du projet
Le mécanisme d’emballage de l’ADN
Les cellules peuvent faire tenir environ deux mètres d’ADN humain dans quelques micromètres. Pour emballer l’ADN dans un espace aussi réduit, il est complexé avec des protéines dans la chromatine qui, à son tour, se plie pour devenir un chromosome. Cette condensation permet également de réguler l’accès à l’information génétique en fonction des besoins de la cellule. Financé par le Conseil européen de la recherche, le projet LoopSMC entend étudier le mécanisme de pliage de l’ADN. Les chercheurs s’intéresseront au processus d’extrusion des boucles et expliqueront le rôle de certaines protéines. Ces travaux offriront un aperçu structurel et dynamique de la fonction et de la cinétique de l’extrusion des boucles dans les processus cellulaires. Ils sont essentiels pour comprendre la structure fondamentale de l’emballage du génome ainsi que sa fonction biologique.
Objectif
Life and evolution of organisms relies on the maintenance, integration, propagation, and readout of genetic information. This information is stored in chromosomes that have a specific three-dimensional structure, a condensed yet accessible form of DNA that is dynamically folded during the lifespan of cells. How DNA is folded within chromosomes has however remained a mystery. It has been proposed that this is achieved by a process of loop extrusion in which SMC (Structural Maintenance of Chromosomes) complexes that are multi-subunit ATPases present in all kingdoms of life – including condensin and cohesin – reel DNA into loops, thereby organizing genomic DNA into higher-order structures. Recent in vitro single-molecule studies, stimulated by our initial discovery on condensin, provided direct evidences that both condensin and cohesin can indeed generate chromatin loops by extrusion. However, the most fundamental questions relating to this process remain unanswered: What is the molecular mechanism of loop extrusion? How is this process regulated? What are the functional roles of SMC-mediated loop extrusion beyond condensation? To address these questions, we will synergistically combine our single-molecule loop extrusion assay with correlative light and electron tomography and force spectroscopy to reveal both dynamic and structural aspects of loop extrusion and SMC proteins. Specifically, we will resolve how SMC complexes function as molecular ‘motors’, how regulatory factors modulate the kinetics of loop extrusion, and how loop extrusion impacts cellular functions like chromosome segregation and gene recombination, all at the single molecule level. In the long term, our findings will provide vital insights into the basic packaging structure of the genome which directly governs its biological function.
Champ scientifique
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Thème(s)
Régime de financement
ERC - Support for frontier research (ERC)Institution d’accueil
80539 Munchen
Allemagne