Cohesins are protein complexes found in nearly all organisms with a nucleus. These complexes play a role in maintaining genome stability and ensuring proper cellular function. Their activities are central to how cells manage and distribute genetic information, impacting processes from cell division to DNA organization within the nucleus. Proper cohesin function is important for the health and development of an organism.
What Cohesins Are
Cohesin is a multi-protein complex with a ring-shaped structure. It is composed of four protein subunits:
Two Structural Maintenance of Chromosomes (SMC) proteins: SMC1 and SMC3
A kleisin protein: RAD21 (also known as SCC1)
A stromal antigen (SA) protein: SA1 or SA2
The SMC proteins, SMC1 and SMC3, form a V-shaped heterodimer by interacting at their hinge domains, with each protein also featuring an ATPase domain. The kleisin subunit, RAD21, acts as a bridge, connecting the ATPase domains of SMC1 and SMC3, thereby closing the protein ring. The SA subunit then associates with RAD21. This ring-like architecture allows cohesin to encircle DNA, which is how it performs its functions. This closed ring is essential for cohesin to entrap DNA strands.
Their Essential Role in Cell Division
Cohesins play an important role in cell division by ensuring that genetic material is accurately distributed to daughter cells. After DNA replication, cohesin complexes encircle and hold sister chromatids together. This physical linkage, known as sister chromatid cohesion, is maintained from the S phase (DNA synthesis phase) until the onset of anaphase during both mitosis and meiosis.
This cohesion is important for accurate chromosome segregation, ensuring each new cell receives a complete set of chromosomes. During prophase in mitosis, cohesin begins to dissociate from chromosome arms, but it remains concentrated at the centromeres, which are constricted regions of the chromosomes. This centromeric cohesion is important for chromosome alignment on the mitotic spindle during metaphase.
Sister chromatids separate during anaphase. At this stage, an enzyme called separase cleaves the RAD21 subunit of the cohesin ring. This cleavage opens the cohesin ring, leading to cohesin dissociation from chromosomes and allowing sister chromatids to be pulled apart to opposite poles of the cell. In meiosis, a specialized form of cohesin, containing the REC8 subunit, also ensures sister chromatid cohesion during two rounds of cell division.
Cohesins Beyond Chromosome Segregation
Cohesins are multifunctional proteins with roles beyond chromosome segregation. These complexes contribute to genome integrity through DNA repair. Cohesins are recruited to sites of DNA damage, particularly double-strand breaks (DSBs), and are important for efficient repair through homologous recombination. This process uses an intact homologous DNA molecule, typically the sister chromatid, as a template to accurately repair the break. Cohesins facilitate this by holding sister chromatids in close proximity, which helps in the search for homologous sequences and ensures that the correct template is used for repair.
Cohesins also influence gene expression by organizing chromosome architecture within the nucleus. Cohesins, often in conjunction with other proteins like CTCF, form chromatin loops that bring distant regulatory elements, such as enhancers and promoters, into close physical proximity. This looping is important for gene activation and regulation. By influencing these long-range interactions, cohesins play a part in determining which genes are active in a particular cell type, contributing to cell identity and development.
The Impact of Cohesin Dysfunction
When cohesins do not function correctly, genomic instability can arise. Errors in cohesin function can result in missegregation of chromosomes during cell division, leading to an incorrect number of chromosomes in daughter cells, a condition known as aneuploidy. Aneuploidy is a hallmark of many human diseases, including various cancers.
Cohesin dysfunction can also cause specific human developmental disorders, termed “cohesinopathies.” Cornelia de Lange Syndrome (CdLS) is the most recognized cohesinopathy, caused by mutations in genes encoding cohesin subunits or their regulators, such as NIPBL, SMC1A, SMC3, RAD21, and HDAC8. Individuals with CdLS often exhibit a range of characteristics, including distinctive facial features, growth and developmental delays, intellectual disability, and limb abnormalities. Cohesin dysfunction can also alter genome structure and gene expression, contributing to disease pathology.