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The Department of Chemical and Systems Biology PresentsSpecial SeminarJan-Michael Peters, PhDScientific Director, Research Institute of Molecular Pathology (IMP), Vienna - BiocenterThursday, October 23, 202510:0 AM – 11:00 AM Munzer Auditorium Talk Title: "How cohesin folds the genome by loop extrusion"Abstract: Cohesin complexes fold genomic DNA by loop extrusion. The chromatin loops formed by this process have important functions in gene regulation, recombination, and DNA damage repair, and defects in cohesin-mediated loop extrusion are thought to contribute to tumorigenesis and congenital ‘cohesinopathies’. ‘Structural maintenance of chromosomes’ (SMC) complexes related to cohesin exist in all kingdoms of life and fold genomic DNA also in eubacteria and archaebacteria. Loop extrusion is therefore an ancient and fundamental process that might have facilitated the evolution of large DNA genomes.Using biochemical reconstitution and single-molecule imaging, we showed that cohesin extrudes DNA into cis-loops (Davidson, Science 2019). This was an unexpected finding since cohesin had initially been discovered for its ability to connect replicated DNA molecules in trans and had been proposed to mediate this sister chromatid cohesion as a passive linker. Our work revealed that the cohesin regulator NIPBL is a processivity factor for loop extrusion and not, as initially proposed, a cohesin loader. We provided direct evidence that CTCF is a directional boundary for cohesin-mediated loop extrusion (Davidson, Nature 2023) and found that cohesin is a unidirectional extruder that can switch the direction of extrusion when NIPBL unbinds and rebinds (Barth, Cell 2025).We identified DNA binding sites and large-scale conformational changes in cohesin and NIPBL that are required for loop extrusion, showed that these are coordinated with cohesin’s ATP binding-hydrolysis cycle (Bauer, Cell 2021) and found that cohesin takes large steps of 100-200 bp during loop extrusion (Davidson, Nature 2023). We further observed that cohesin negatively supercoils DNA during loop extrusion and found that topoisomerase I is required for the formation of long cohesin loops in cells (Davidson, Cell Rep. 2025).The length and lifetime of loops formed by cohesin (‘cohesin loops’) is limited by WAPL, which can release cohesin from chromatin (Kueng, Cell 2006; Tedeschi, Nature 2013; Wutz, EMBO J., 2017; see also Haarhuis, Cell 2017), whereas the position of cohesin loops in the genome is determined by boundary elements, such as CTCF (Wendt, Nature 2008; Busslinger, Nature 2017; Wutz, EMBO J., 2017; see also Nora, Cell 2017). We had found earlier that PDS5 proteins are also required for CTCF boundaries (Wutz, EMBO J., 2017). We now discovered that PDS5 proteins contribute to this function by facilitating the dissociation of NIPBL from cohesin, thus limiting the lifetime of these complexes (Wutz, bioRxiv 2025).
📍 Munzer Auditorium