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.
Keywords: Cohesin; DNA loop extrusion; S. pombe; SMC complexes; biophysical simulation; chromosomes; computational biology; gene expression; sister chromatid cohesion; structural biology; systems biology.
When a cell divides, it has to ensure that each of its daughter cells inherits one copy of its genetic information. It does this by duplicating its chromosomes (the DNA molecules that encode the genome) and distributing one copy of each to its daughter cells. Once a cell duplicates a chromosome, the two identical chromosomes must be held together until the cell is ready to divide in two. A ring-shaped protein complex called cohesin does this by encircling the two chromosomes. Cohesin embraces both chromosome copies, as they emerge from the DNA replicating machinery. The complex is formed of several proteins that bind to a small molecule called ATP, whose arrival and subsequent breakdown release energy. Cohesin also interacts with DNA in a different way: it can create loops of chromatin (the complex formed by DNA and its packaging proteins) that help regulate the activity of genes. Experiments performed on single molecules isolated in the laboratory show that cohesin can form a small loop of DNA that is then enlarged through a process called DNA loop extrusion. However, it is not known whether loop extrusion occurs in the cell. Although both of cohesin’s roles have to do with how DNA is organised in the cell, it remains unclear how a single protein complex can engage in two such different activities. To answer this question, Higashi et al. used a structure of cohesin from yeast cells gripping onto DNA to build a model that simulates how the complex interacts with chromosomes and chromatin. This model suggested that when ATP is broken down, the cohesin structure shifts and DNA enters the ring, allowing DNA to be entrapped and chromosomes to be bound together. However, a small change in how DNA is gripped initially could prevent it from entering the ring, creating a ratchet mechanism that forms and enlarges a DNA loop. This molecular model helps explain how cohesin can either encircle DNA or create loops. However, Higashi et al.’s findings also raise the question of whether loop extrusion is possible inside cells, where DNA is densely packed and bound to proteins which could be obstacles to loop extrusion. Further research to engineer cohesin that can only perform one of these roles would help to clarify their individual contributions in the cell.
© 2021, Higashi et al.