Loop extrusion is a major mechanism of nuclear organization. It is a dynamic process in which structural maintenance of chromosomes (SMC) protein complexes progressively grow loops of DNA or chromatin. In this process, SMC complexes, such as condensin or cohesin, bind to DNA/chromatin, use ATP-driven motor activity to reel in DNA, and as a result, extrude the collected DNA as a loop.
Background The organization of DNA presents a remarkable biological challenge: human DNA can reach 2 meters and is packed into the nucleus with the diameter of 5-20 μm. At the same time, the critical cell processes involve complex processes on highly compacted DNA, such as transcription, replication, recombination, DNA repair, and cell division. Loop extrusion is a key mechanism that organizes DNA into loops, enabling its efficient compaction and functional organization. For instance, in vitro experiments show that cohesin can compact DNA by 80%, while condensin achieves a remarkable 10,000-fold compaction of mitotic chromosomes, as evidenced by microscopy, Hi-C, and polymer simulations. Another challenge lies in establishing long-range genomic communication, which can span hundreds of thousands of base pairs. Physical encounters between genomic elements are intrinsically random and promiscuous without mechanisms to facilitate them. Loop extrusion has been proposed to provide an effective solution to regulate contacts by bringing target elements into proximity while limiting contact with unwanted loci.
Key components The key components of the loop extrusion process are
DNA molecule that serves as the substrate for the movement of extruder Extruders, usually SMC complexes, that moves along DNA in ATP-dependent manner Accessory factors Loaders of the extruder, a factor that facilitates loading of extruder on DNA (NIPBL/MAU2 are thought to play the key role in loading extruder on DNA) Unloaders of the extruder, the molecule that facilitates detachment of extruder from DNA (for example, WAPL) Road-blocks located on DNA that present a hindrance to extruder movement and lead to stalling of the extrusion machinery.
SMC proteins
Loop extrusion is performed by the SMC family of protein-complexes which includes cohesin, condensin, and SMC5/6 each playing specialized roles depending on the organism, cell cycle phase, and biological context. Cohesin mediates chromatin loop formation and stabilization, particularly during interphase in vertebrates, where it facilitates transcriptional regulation by promoting distal enhancer-promoter interactions. During mitosis and meiosis, cohesin dissociates from chromosome arms ceding its loop extrusion role to condensin. Loop extrusion by condensin mediates large-scale chromosome compaction, creating the compact, rod-like chromosome structures required for accurate segregation. Unlike cohesin and condensin, SMC5/6 is a loop extruding factor which primarily functions in maintaining genome integrity during DNA damage repair and resolving replication stress. Despite their distinct roles, SMC complexes share a highly conserved ring-like structure. Two SMC proteins (usually, SMC1 and SMC3) are connected via a hinge region and linked at their heads by a kleisin subunit, forming a closed ring. These two SMC proteins have ATPase domains at their heads, which bind together and hydrolyze ATP. Cycles of ATP binding and hydrolysis mediate conformational changes in the ring structure, driving DNA translocation and stepwise loop extrusion. ATP is essential for both initiating loop extrusion (e.g., loading SMC complexes onto DNA) and propagating it (growing loops by translocating along DNA). The tension within the DNA significantly influences extrusion efficiency. At low tension, SMC complexes can make larger loop-capture steps, while higher tension can lead to stalling or reversal of loop extrusion.
Modifications and factors for loading/unloading The dynamic nature of loop extrusion is tightly controlled by accessory factors and post-translational modifications, especially in the case of cohesin. In vertebrates, NIPBL (and orthologs like Mau2 in yeast or SCC2 and SCC4) is crucial for loading SMC complexes onto DNA, initiating and maintaining active extrusion. PDS5 is thought to pause the extrusion process. The SMC can then either restart extruding or be unloaded by the additional binding of WAPL, which ensure proper recycling and turnover. Post-translational modifications also play a key role. Acetylation of cohesin by enzymes such as ESCO1 and ESCO2 stabilizes chromatin loops, particularly at CTCF-bound sites. Similarly, SUMOylation, mediated by the NSE2 subunit of the SMC5/6 complex, enhances the recruitment of SMC5/6 to sites of DNA damage, supporting its role in genomic stability.
Roadblocks of loop extrusion Loop extruders can encounter various obstacles while extruding. For example, many of which were shown to directly interact with cohesin and hypothesized to stop its movement on DNA. However, in vivo experiments demonstrate that cohesin can frequently bypass obstacles larger than its ring size.
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