Project description
Mechanistic insight into DNA packaging
Cells can fit approximately two metres of human DNA into a few micrometres. To package DNA into such a tiny space, it is complexed with proteins into chromatin which, in turn, folds into chromosomes. This condensation also helps regulate access to genetic information according to cell needs. Funded by the European Research Council, the LoopSMC project aims to investigate the mechanism by which DNA is folded. Researchers will focus on the process of loop extrusion and elucidate the role of specific proteins. The work will provide both structural and dynamic insight into the function and kinetics of loop extrusion in cellular processes. This is essential to understanding the fundamental packaging structure of the genome and its biological function.
Objective
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.
Fields of science
Programme(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Topic(s)
Funding Scheme
ERC - Support for frontier research (ERC)Host institution
80539 Munchen
Germany