Descripción del proyecto
Información mecanicista sobre el empaquetamiento del ADN
Las células pueden albergar aproximadamente dos metros de ADN humano en unos pocos micrómetros. Para empaquetar el ADN en un espacio tan minúsculo, se forma un complejo con proteínas denominado cromatina que, a su vez, se pliega en cromosomas. Esta condensación también ayuda a regular el acceso a la información genética en función de las necesidades celulares. El objetivo del proyecto LoopSMC, financiado por el Consejo Europeo de Investigación, es investigar el mecanismo por el que se pliega el ADN. Los investigadores se centrarán en el proceso de extrusión de bucles y dilucidarán el papel de proteínas específicas. El trabajo proporcionará una visión tanto estructural como dinámica de la función y la cinética de la extrusión de bucles en los procesos celulares. Esta información es esencial para comprender la estructura de empaquetamiento fundamental del genoma y su función biológica.
Objetivo
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.
Ámbito científico
Programa(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régimen de financiación
ERC - Support for frontier research (ERC)Institución de acogida
80539 Munchen
Alemania