Cohesin supercoils DNA during loop extrusion

• Published in: Cell reports (Cambridge) Vol. 44; no. 6; p. 115856
• Main Authors: Davidson, Iain F., Barth, Roman, Nagasaka, Kota, Tang, Wen, Wutz, Gordana, Horn, Sabrina, Janissen, Richard, Stocsits, Roman R., Chlosta, Emilia, Bauer, Benedikt W., Dekker, Cees, Peters, Jan-Michael
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.06.2025
• Subjects: Cell Cycle Proteins - chemistry; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Chromosomal Proteins, Non-Histone - chemistry; Chromosomal Proteins, Non-Histone - genetics; Chromosomal Proteins, Non-Histone - metabolism; cohesin; Cohesins; DNA, Superhelical - chemistry; DNA, Superhelical - genetics; DNA, Superhelical - metabolism; loop extrusion; Nucleic Acid Conformation; SMC complexes; supercoiling; topoisomerases; CP: Molecular biology; topoisomerases; cohesin; SMC complexes; loop extrusion; supercoiling
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2025.115856

Cohesin extrudes genomic DNA into loops that promote chromatin assembly, gene regulation, and gene recombination. Loop extrusion depends on large-scale conformational changes in cohesin, but how these translocate DNA is poorly understood. Here, we provide evidence that cohesin negatively supercoils DNA during loop extrusion. Supercoiling requires the engagement of cohesin’s ATPase heads, DNA clamping by these heads, and a DNA-binding site on cohesin’s hinge, indicating that cohesin twists DNA when constraining it between the hinge and the clamp. A cohesin mutant defective in negative supercoiling forms shorter loops in cells, and a similar, although weaker, phenotype is observed after the depletion of topoisomerase I. These results suggest that supercoiling is an integral part of the loop-extrusion mechanism and that relaxation of supercoiled DNA is required for cohesin-mediated loop extrusion and genome architecture. [Display omitted] •Cohesin twists DNA while constraining it between the hinge and the clamp•The torque required for twisting depends on the DNA-binding affinity of the clamp•Topoisomerase I is required for formation of long cohesin loops in cells Davidson et al. show that cohesin negatively supercoils DNA. In vitro, this process depends on the same DNA-binding sites and co-factors as cohesin’s loop-extrusion activity, and a cohesin mutant defective in negative supercoiling forms shorter loops in cells. These results indicate that cohesin supercoils DNA during loop extrusion.