Cohesin is a fundamental protein complex in all eukaryotic cells, acting as a molecular tether necessary for maintaining the integrity of the genetic material. This large, ring-shaped structure physically holds together newly copied DNA molecules. Its proper operation is required for accurate cell division and the correct organization of DNA within the nucleus. Cohesin’s ability to manage DNA structure and segregation makes it a central player in cellular life, influencing gene activity and the prevention of genetic disorders.
The Molecular Architecture and Function
Cohesin is a multi-subunit protein complex assembled into a large, closed ring structure. The core consists of four proteins: two Structural Maintenance of Chromosomes (SMC) proteins (SMC1 and SMC3), and two non-SMC proteins (SCC1/Rad21 and a Stromal Antigen subunit, SA1 or SA2). The SMC proteins form a V-shaped heterodimer with long, coiled-coil arms connected by a flexible hinge domain. The heads of the SMC proteins contain ATPase domains and link to the non-SMC subunits to complete the ring.
The physical mechanism by which Cohesin performs its primary task is called sister chromatid cohesion. Following DNA replication during the S phase, the Cohesin ring entraps the two identical double-helix DNA molecules, known as sister chromatids. This embrace ensures the two DNA copies remain physically linked along their length until cell division.
For cohesion to be established, the ring must first be loaded onto the chromosomes, mediated by the NIPBL-MAU2 complex. Once loaded, the SMC3 subunit is acetylated by the enzyme ESCO1 or ESCO2. This acetylation converts the Cohesin ring into a stable, cohesion-competent state resistant to immediate release. This process locks the sister chromatids together, ensuring the cell treats the two duplicated DNA strands as a single unit ready for mitosis.
Regulating the Cell Cycle
The Cohesin complex acts as the molecular timer for chromosome segregation, controlling the precise moment when duplicated chromosomes separate during cell division. In metazoan cells, Cohesin is removed from the chromosome arms in a two-step process to prepare the cell for division.
This initial release is driven by the Wapl-Pds5 protein complex, which modulates the ATPase activity of the SMC subunits. This modulation leads to the opening of the Cohesin ring’s gate, allowing the DNA to escape. This action resolves the bulk of the sister chromatids, leaving only the centromeric regions tethered, which are protected from Wapl-mediated release by the protein Shugoshin (Sgo1).
The final, irreversible separation is triggered only when the cell confirms all chromosomes are correctly attached to the spindle apparatus, regulated by the Spindle Assembly Checkpoint. Once satisfied, the enzyme Separase is activated. Separase is a protease that cleaves the SCC1/Rad21 subunit, breaking the Cohesin ring and dissolving the physical link between the sister chromatids. This cleavage allows the two sister chromatids to be pulled toward opposite poles of the cell, completing accurate chromosome segregation.
Influence on DNA Organization and Gene Expression
Beyond cell division, Cohesin shapes the three-dimensional organization of the genome during non-dividing phases. The complex is a central component in forming chromatin loops and Topologically Associated Domains (TADs), which are genomic regions that interact frequently with themselves. This structural organization is achieved through the loop extrusion model, where the Cohesin ring actively motorizes along the DNA.
As Cohesin moves, it acts like a winch, capturing and reeling in the chromatin fiber to generate progressively larger loops. This process compacts the DNA and brings distant regions of the genome into close physical proximity.
The boundaries of these TADs and loops are defined by the DNA-binding protein CTCF. CTCF acts as a roadblock, stalling the loop-extruding action of Cohesin when the two proteins meet in a convergent orientation.
The formation of these loops and domains regulates gene expression. By folding the DNA, Cohesin bridges regulatory elements, such as enhancers, with the promoters of the genes they control, even if they are hundreds of thousands of base pairs apart. This physical juxtaposition controls which genetic programs are active, influencing cell fate and identity.
When Cohesin Fails: Cohesinopathies and Disease
Disruptions in the Cohesin complex or its regulatory proteins cause a group of developmental disorders called Cohesinopathies. The most studied is Cornelia de Lange Syndrome (CdLS), characterized by craniofacial abnormalities, growth retardation, and limb malformations. CdLS is caused primarily by mutations in the cohesin-loading protein NIPBL (accounting for approximately 60% of cases), as well as mutations in the core subunits SMC1A and SMC3.
These mutations cause a partial reduction in Cohesin activity, leading to defects in sister chromatid cohesion and gene regulation. The resulting misregulation of developmental gene expression during embryogenesis causes the physical symptoms observed in affected individuals.
Cohesin dysfunction is also implicated in the development of cancer. Somatic mutations in Cohesin genes are frequently observed in human tumors, particularly the STAG2 gene (coding for the SA-2 subunit) in bladder cancer, glioblastoma, and myeloid malignancies. These mutations promote aneuploidy—an abnormal number of chromosomes—by causing errors during chromosome segregation.
This chromosomal instability (CIN) is a hallmark of many cancers, including the majority of colorectal cancers. Missegregation events lead to the loss or gain of entire chromosomes that may carry tumor suppressor genes or proto-oncogenes.