Establishment of sister chromatid cohesion

Sister chromatid cohesion refers to the process by which sister chromatids are paired and held together during certain phases of the cell cycle. Establishment of sister chromatid cohesion is the process by which chromatin-associated cohesin protein becomes competent to physically bind together the sister chromatids. In general, cohesion is established during S phase as DNA is replicated, and is lost when chromosomes segregate during mitosis and meiosis. Some studies have suggested that cohesion aids in aligning the kinetochores during mitosis by forcing the kinetochores to face opposite cell poles. Sister chromatid cohesion refers to the process by which sister chromatids are paired and held together during certain phases of the cell cycle. Establishment of sister chromatid cohesion is the process by which chromatin-associated cohesin protein becomes competent to physically bind together the sister chromatids. In general, cohesion is established during S phase as DNA is replicated, and is lost when chromosomes segregate during mitosis and meiosis. Some studies have suggested that cohesion aids in aligning the kinetochores during mitosis by forcing the kinetochores to face opposite cell poles. Cohesin first associates with the chromosomes during G1 phase. The cohesin ring is composed of two SMC (structural maintenance of chromosomes) proteins and two additional Scc proteins. Cohesin may originally interact with chromosomes via the ATPase domains of the SMC proteins. In yeast, the loading of cohesin on the chromosomes depends on proteins Scc2 and Scc4. Cohesin interacts with the chromatin at specific loci. High levels of cohesin binding are observed at the centromere. Cohesin is also loaded at cohesin attachment regions (CARs) along the length of the chromosomes. CARs are approximately 500-800 base pair regions spaced at approximately 9 kilobase intervals along the chromosomes. In yeast, CARs tend to be rich in adenine-thymine base pairs. CARs are independent of origins of replication. Establishment of cohesion refers to the process by which chromatin-associated cohesin becomes cohesion-competent. Chromatin association of cohesin is not sufficient for cohesion. Cohesin must undergo subsequent modification ('establishment') to be capable of physically holding the sister chromosomes together. Though cohesin can associate with chromatin earlier in the cell cycle, cohesion is established during S phase. Early data suggesting that S phase is crucial to cohesion was based on the fact that after S phase, sister chromatids are always found in the bound state. Tying establishment to DNA replication allows the cell to institute cohesion as soon as the sister chromatids are formed. This solves the problem of how the cell might properly identify and pair sister chromatids by ensuring that the sister chromatids are never separate once replication has occurred. The Eco1/Ctf7 gene (yeast) was one of the first genes to be identified as specifically required for the establishment of cohesion. Eco1 must be present in S phase to establish cohesion, but its continued presence is not required to maintain cohesion. Eco1 interacts with many proteins directly involved in DNA replication, including the processivity clamp PCNA, clamp loader subunits, and a DNA helicase. Though Eco1 contains several functional domains, it is the acetyltransferase activity of the protein which is crucial for establishment of cohesion. During S phase, Eco1 acetylates lysine residues in the Smc3 subunit of cohesin. Smc3 remains acetylated until at least anaphase. Once cohesin has been removed from the chromatin, Smc3 is deacetylated by Hos1. The Pds5 gene was also identified in yeast as necessary for the establishment of cohesion. In humans, the gene has two homologs, Pds5A and Pds5B. Pds5 interacts with chromatin-associated cohesin. Pds5 is not strictly establishment-specific, as Pds5 is necessary for maintenance of cohesion during G2 and M phase. The loss of Pds5 negates the requirement for Eco1. As such, Pds5 is often termed an 'anti-establishment' factor. In addition to interacting with cohesin, Pds5 also interacts with Wapl (wings apart-like), another protein that has been implicated in the regulation of sister chromatid cohesion. Human Wapl binds cohesin through the Scc cohesin subunits (in humans, Scc1 and SA1). Wapl has been tied to the loss of cohesin from the chromatids during M phase. Wapl interacts with Pds5 through phenylalanine-glycine-phenylalanine (FGF) sequence motifs. One model of establishment of cohesion suggests that establishment is mediated by the replacement of Wapl in the Wapl-Pds5-cohesin complex with the Sororin protein. Like Wapl, Sororin contains an FGF domain and is capable of interacting with Pds5. In this model, put forward by Nishiyama et al., Wapl interacts with Pds5 and cohesin during G1, before establishment. During S phase, Eco1 (Esco1/Esco2 in humans) acetylates Smc3. This results in recruitment of Sororin. Sororin then replaces Wapl in the Pds5-cohesin complex. This new complex is the established, cohesion-competent cohesin state. At entry to mitosis, Sororin is phosphorylated and replaced again by Wapl, leading to loss of cohesion. Sororin also has chromatin binding activity independent of its ability to mediate cohesion. Cohesion proteins SMC1ß, SMC3, REC8 and STAG3 appear to participate in the cohesion of sister chromatids throughout the meiotic process in human oocytes. SMC1ß, REC8 and STAG3 are meiosis specific cohesin proteins. The STAG3 protein is essential for female meiosis and fertility.