What Are the Functions of Cohesin in the Cell?

The proper distribution of genetic material is fundamental for all life. At the heart of this process is the cohesin complex, a group of proteins often described as molecular glue. Cohesin physically holds DNA strands together, ensuring each new cell receives a complete genetic blueprint during division. The complex’s role also extends beyond division, influencing how DNA is organized and repaired.

The Cohesin Complex

Cohesin’s function is tied to its physical structure as a multi-subunit protein complex that forms a large ring. This ring is composed of four core protein subunits highly conserved in eukaryotes, from yeast to humans. Two subunits, SMC1 and SMC3, are long proteins that connect at one end through a flexible hinge, forming a V-like shape.

The open ends of the SMC “V” are bridged by a third protein, RAD21, which closes the ring. A fourth subunit, a STAG protein, associates with RAD21 and helps regulate the complex’s function. This ring structure can be opened and closed at the junction between the SMC proteins and RAD21, allowing it to be loaded onto and removed from chromosomes.

Holding Chromosomes Together During Cell Division

Cohesin’s primary function is connecting sister chromatids. After a cell replicates its DNA, it has two identical copies of each chromosome, called sister chromatids, which must stay paired until separation. The cohesin complex is loaded onto chromosomes before DNA replication, and as replication proceeds, the rings entrap the newly synthesized sister chromatids, linking them together.

This connection is maintained through the G2 phase and into mitosis. As chromosomes condense and align at the cell’s center during metaphase, the cohesin rings hold the sister chromatids together. This tethering ensures spindle fibers can attach correctly to each sister chromatid before they are pulled apart.

Separation is triggered during anaphase when an enzyme called separase becomes active and cleaves the RAD21 subunit. This action is like cutting a zip tie, instantly breaking the link between the sister chromatids. Once freed, the chromatids are pulled to opposite poles of the dividing cell, ensuring each resulting daughter cell inherits a complete set of chromosomes. A similar, more intricate process occurs during meiosis, the cell division that produces sperm and egg cells.

Cohesin’s Role in DNA Organization and Repair

Beyond cell division, cohesin helps organize the genome’s three-dimensional structure. DNA must be folded to fit inside the nucleus, and this organization affects which genes are active. Working with a protein called CTCF, cohesin forms chromatin loops by bringing distant DNA segments together. These loops can isolate genomic neighborhoods, allowing genes inside to be regulated independently from those outside.

Cohesin also contributes to DNA repair. When DNA suffers a double-strand break, the cell can use the undamaged sister chromatid as a template for repair in a process called homologous recombination. Cohesin holds the broken ends close and tethers the damaged chromatid to its intact sister. This facilitates the repair machinery’s access to the correct template during the S and G2 phases of the cell cycle.

When Cohesin Fails: Cohesinopathies

Malfunctions in the cohesin complex can have severe consequences. If cohesin fails to hold sister chromatids together during cell division, it can lead to aneuploidy, a condition where cells receive an incorrect number of chromosomes. This can result in cell death or contribute to cancer development.

Mutations in the genes for cohesin subunits or its regulators cause rare genetic disorders known as cohesinopathies. The most well-studied is Cornelia de Lange syndrome (CdLS), a developmental disorder with a wide range of challenges. The features can include:

• Distinctive facial characteristics
• Growth delays
• Limb abnormalities
• Intellectual disability