Cohesin mediates DNA loop extrusion by a “swing and clamp” mechanism

Structural maintenance of chromosomes (SMC) complexes organize genome topology in all kingdoms of life and have been proposed to perform this function by DNA loop extrusion. How this process works is unknown. Here, we have analyzed how loop extrusion is mediated by human cohesin-NIPBL complexes, which enable chromatin folding in interphase cells. We have identified DNA binding sites and large-scale conformational changes that are required for loop extrusion and have determined how these are coordinated. Our results suggest that DNA is translocated by a spontaneous 50 nm-swing of cohesin’s hinge, which hands DNA over to the ATPase head of SMC3, where upon binding of ATP, DNA is clamped by NIPBL. During this process, NIPBL “jumps ship” from the hinge toward the SMC3 head and might thereby couple the spontaneous hinge swing to ATP-dependent DNA clamping. These results reveal mechanistic principles of how cohesin-NIPBL and possibly other SMC complexes mediate loop extrusion. [Display omitted] •Identification of cohesin’s DNA binding sites and movements needed for loop extrusion•A DNA binding site on the hinge might translocate DNA by ATP-independent swinging•DNA clamping on the ATPase heads is regulated by ATP-dependent engagement cycles•NIPBL couples ATP-independent and -dependent DNA translocation events Cohesin hands DNA over long distances from one binding site to another, explaining how SMC complexes might fold genomes in all kingdoms of life.