NIPBL and STAG1 enable loop extrusion by providing differential DNA-cohesin affinity.
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| Title: | NIPBL and STAG1 enable loop extrusion by providing differential DNA-cohesin affinity. |
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| Authors: | van Wee, Raman, Asor, Roi, Yiwen Li, Drechsel, David, Popova, Mariia, Litos, Gabriele, Davidson, Iain F., Peters, Jan-Michael, Kukura, Philipp |
| Source: | Proceedings of the National Academy of Sciences of the United States of America; 8/12/2025, Vol. 122 Issue 32, p1-8, 39p |
| Subject Terms: | SINGLE molecules, HETERODIMERS, COHESINS, PROTEIN-protein interactions, BINDING sites |
| Abstract: | DNA loop extrusion by cohesin has emerged as a critical pathway for chromosome organization. In vitro single-molecule experiments indicate that loop extrusion requires the assembly of a heteropentameric complex consisting of the SMC1/SMC3 heterodimer, STAG1, NIPBL, and the kleisin SCC1. The complexity of the complete extrusion machinery, consisting of multiple subunits, DNA binding sites, and ATPases poses substantial challenges for revealing the underlying biomolecular mechanism. As a result, a number of different models have been proposed, many of which do not agree on key mechanistic aspects, such as the details of DNA loading, holoenzyme assembly, or the consequences of ATP binding and hydrolysis. Here, we use mass photometry to comprehensively quantify all the key biomolecular interactions required for DNA loop extrusion. We find that STAG1 binds tightly to the trimeric complex formed by the SMC1/SMC3 heterodimer and SCC1, and together they weakly, but cooperatively, bind the DNA. Full-length NIPBL tightly binds DNA, acting as a DNA anchor during the mechanochemical loop extrusion cycle. Cohesin mutants incapable of head engagement, and those lacking DNA-binding domains in the ATPase heads show negligible differences in overall DNA-affinity, suggesting a minor role of these features for DNA binding. Instead, we find an ATP-modulated DNA binding site created by the interaction of STAG1 with SMC1/SMC3/SCC1, important for repeated grabbing and release of DNA critical to extrusion. Our results call for a careful reexamination of the proposed mechanisms and set energetic boundaries for future proposals. [ABSTRACT FROM AUTHOR] |
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| Database: | Complementary Index |
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