18.3: Cohesins

Cohesin protein complexes are a molecular glue that holds two sister chromatids together. They play an important role both in mitosis and meiosis. In mitosis, all cohesin complexes present on the chromosomes are removed before the start of the anaphase stage.

Cohesin complexes in Meiotic Division

Meiosis involves two distinct rounds of chromosomal segregation and cell divisions— Meiosis I followed by Meiosis II – producing four daughter cells. Meiosis I includes the separation of homologous chromosomes, whereas Meiosis-II involves the separation of sister chromatids.

The Meiosis I cohesin complex consists of four subunits – Smc1, Smc3, Rec8 (replacing Scc1 from mitotic cohesin complex), and Scc3 – forming a ring-like structure.

During Meiosis I, entire chromosomes segregate towards the opposite poles as cohesin removal takes place only from the chromosomal arms. Cohesin is still maintained at the centromere region, allowing the sister chromatids to remain connected. During the metaphase I to anaphase I transition, the differential cohesin removal is facilitated by the separase-mediated cleavage of the Rec8 subunit of cohesins along the chromosomal arms. The centromeric Rec8 is protected from cleavage by association with a protector protein Shugoshin (Sgo1).

Cohesinopathies

Cohesins contribute to the maintenance of genomic stability. Mutations in genes coding for cohesin subunits or cohesin co-factors can lead to diseases called cohesinopathies. Cornelia de Lange syndrome (CdLS) and Roberts syndrome are two best-described cohesinopathies. CdLS is a neurodevelopmental disorder causing mental retardation, facial dysmorphism, upper limb abnormalities, and growth delay. Roberts syndrome results in craniofacial abnormalities, limb reduction, and growth retardation in affected patients.

During S-phase of the cell cycle in eukaryotes, chromosomal duplication produces two identical copies of each chromosome called sister chromatids.

The sister chromatids formed are held together by a set of protein complexes called cohesins. The cohesin rings exist as clamps around the sister chromatids at multiple locations along their length, preventing them from drifting apart.

Cohesin complexes contain four subunits: Smc1, Smc3, Scc1, and Scc3. The Smc1 and Smc3 are coiled-coil proteins with a hinge domain at one end and an ATPase head domain at the other end. The hinge domains of Smc1 and Smc3 bind directly to each other, while an Scc1 subunit connected to an Scc3 subunit bridges the head domains of Smc1 and Smc3, forming a ring-like structure.

The hinge domain of the cohesin ring-structure can be triggered to open and close, facilitating cohesin loading on the chromosomes.

As cells progress through mitotic prophase, sister chromatid resolution takes place, involving dissociation of cohesin rings along the chromosomal arms while preserving those bound to the centromere region. The differential removal of cohesins causes the sister chromatids to become partially separated along their arms while remaining bound at their centromere.

Chromatid cohesion at the centromere facilitates the bi-orientation of chromosomes on the mitotic spindle during metaphase, ensuring correct microtubule attachment to the kinetochores of the sister chromatids.

At the onset of anaphase, a protease enzyme, separase, cleaves the Scc1 subunit, leading to the dissociation of cohesin from the chromosome.

Cohesin dissociation permits the segregation of sister chromatids during anaphase, where they are pulled apart by mitotic spindles to opposite poles of the cell, eventually leading to cell division and formation of two daughter cells.