A Brownian ratchet model for DNA loop extrusion by the cohesin complex

Abstract

The cohesin complex topologically encircles DNA to promote sister chromatid cohesion. Alternatively, cohesin extrudes DNA loops, thought to reflect chromatin domain formation. Here, we propose a structure-based model explaining both activities. ATP and DNA binding promote cohesin conformational changes that guide DNA through a kleisin N-gate into a DNA gripping state. Two HEAT-repeat DNA binding modules, associated with cohesin’s heads and hinge, are now juxtaposed. Gripping state disassembly, following ATP hydrolysis, triggers unidirectional hinge module movement, which completes topological DNA entry by directing DNA through the ATPase head gate. If head gate passage fails, hinge module motion creates a Brownian ratchet that, instead, drives loop extrusion. Molecular-mechanical simulations of gripping state formation and resolution cycles recapitulate experimentally observed DNA loop extrusion characteristics. Our model extends to asymmetric and symmetric loop extrusion, as well as z-loop formation. Loop extrusion by biased Brownian motion has important implications for chromosomal cohesin function.

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

“…Together with the cyclic DNA clamping described above, these results indicate that not only SMC1 and SMC3, but also NIPBL, undergoes major conformational changes and/or changes in its position relative to other subunits during cohesin’s ATP binding-hydrolysis cycle ( Figure 7 F; note that conformational changes in fungal NIPBL orthologs have also been suggested based on comparisons of crystal and cryo-EM structures) ( Higashi et al., 2021 ). In the absence of ATP (i.e., when cohesin’s ATPase heads are disengaged and the DNA clamp is disassembled), NIPBL’s nose is located in close proximity to the hinge; in the presence of ATP (i.e., when the heads can engage), NIPBL’s body clamps DNA onto the ATPase heads, but the hinge and NIPBL’s nose separate from each other.…”

“…It is also possible that DNA is translocated into the opposite direction (i.e., from the ATPase heads toward the hinge), as has been proposed based on modeling and the speculation that STAG1 moves with the hinge ( Higashi et al., 2021 ). Note that our smFRET experiments failed to detect stable interactions between the hinge and STAG1 and thus do not support this speculation ( Figures S7 E–S7G).…”

A hold-and-feed mechanism drives directional DNA loop extrusion by condensin

“…A central challenge to all models that attempt to describe the mechanism of DNA loop extrusion is that they need to explain how such large consecutive steps proceed in a directional manner on a DNA substrate that lacks intrinsic polarity ( 32 ). Recent “swing and clamp” ( 29 ) or Brownian ratchet ( 33 ) models predict that distant DNA binding sites, created by HEAT-repeat subunits at the SMC hinge and head modules, are brought into the vicinity upon coiled-coil folding. The DNA-segment-capture model ( 34 ), by contrast, suggests that SMC dimers grasp DNA loops that are generated by random thermal motion between their coiled coils and then merge the entrapped loop with a second loop that is held at the head module upon zipping up of the coils.…”

The Interplay of Cohesin and RNA Processing Factors: The Impact of Their Alterations on Genome Stability

“…In addition to the function of cohesin in the regulation of sister chromatid separation [ 45 , 46 ], it also plays important roles in other cellular processes, such as DNA replication, DNA damage repair, the regulation of gene expression, and spatial chromosome organization [ 47 , 48 , 49 , 50 , 51 , 52 , 53 ]. Importantly, recent studies have suggested that cohesin also functions as a molecular motor, catalyzing the extrusion of DNA into the loops, and thus directly regulates genome organization [ 54 , 55 , 56 , 57 , 58 ]. Furthermore, a recent analysis of the genetic interactions between cohesin-complex-related genes and >1400 genes in the S. cerevisiae revealed 373 novel genetic interactions, suggesting the involvement of cohesin-related proteins in such biological processes as post-replication DNA repair, microtubule organization, and protein folding [ 59 ].…”