Our cells contain genetic material organized into structures called chromosomes. Before a cell can divide, this genetic material must be precisely duplicated through a process known as DNA replication. This replication results in two identical copies of each chromosome, referred to as sister chromatids. For accurate distribution into new daughter cells, these replicated chromatids must remain physically linked until the exact moment of cell division.
The Cohesin Complex
The primary molecular structure responsible for holding sister chromatids together is a multi-protein assembly known as the cohesin complex. This complex forms a ring-shaped structure that physically links the two identical DNA molecules.
The cohesin complex consists of four core subunits: Smc1, Smc3, Scc1 and Scc3. The Smc1 and Smc3 proteins are part of the Structural Maintenance of Chromosomes (SMC) family, characterized by long, coiled-coil arms and ATPase head domains. The Scc1 subunit bridges the ATPase heads of Smc1 and Smc3, creating a closed, tripartite ring.
The Mechanism of Cohesion
The cohesin complex establishes its hold on DNA during the S-phase of the cell cycle, coinciding with DNA replication. During this time, cohesin is loaded onto the chromosomes, a process that involves other proteins like SCC2/4. The prevailing “ring model” suggests that the cohesin complex encircles DNA molecules from both sister chromatids, physically trapping them within its central pore. This topological entrapment maintains cohesion.
Cohesin’s interaction with DNA is not static; it can dynamically associate with chromatin. Its primary function involves holding the sister chromatids together. This mechanism ensures that as DNA replication progresses, the newly formed sister chromatids are immediately linked. Both pre-existing cohesin and newly loaded cohesin contribute to establishing this link during S-phase.
Releasing Chromatids for Division
For cell division to proceed correctly, the tight bond between sister chromatids must be precisely released at the appropriate time, specifically during anaphase. This separation is orchestrated by an enzyme called separase. Separase functions as a protease, cleaving a specific subunit of the cohesin complex, Scc1.
The cleavage of Scc1 by separase effectively opens the ring-shaped cohesin complex. Once the ring is broken, the physical link holding the sister chromatids together is dissolved, allowing them to separate and move to opposite poles of the dividing cell. There is also a protective mechanism at the centromeres, the constricted region of a chromosome, where a protein called shugoshin helps to shield cohesin from premature removal. Shugoshin ensures that centromeric cohesin remains intact until later in mitosis, providing an additional layer of control over chromosome segregation.
The Importance of Precise Cohesion
Accurate sister chromatid cohesion and its timely release are important for the proper functioning of cells and the overall health of an organism. Errors in either the establishment or the dissolution of cohesion can lead to serious consequences. Such mistakes can result in aneuploidy, a condition characterized by an abnormal number of chromosomes in cells.
Aneuploidy is associated with various developmental disorders. It also plays a significant role in the development and progression of cancer. The precise regulation of cohesin ensures that each daughter cell receives a complete and correct set of genetic information, thereby maintaining genomic stability.