Chromosome Cohesion: A Cycle of Holding Together and Falling Apart

A ll organisms have mechanisms to ensure that dividing cells produce new cells with the proper number of chromosomes. The dividing cell closely monitors that chromosomes are copied exactly once and then distributed correctly to daughter cells. After replication, the chromosomes (now comprising two chromatids) align at the center of the cell, and are attached to a structure known as the spindle apparatus. A key point of attachment is the centromere, a characteristic constriction carried by each chromosome. The spindle, which is composed of microtubules, pulls the chromatids apart so that two complete sets of chromosomes are gathered together at each pole of the cell, which can then divide. Cohesion between chromosome copies, which keeps the chromatids together until just the right time, therefore plays a critical part in this process. Chromosome cohesion is established during S phase (when the chromosomes are replicated) and is then dissolved completely in metaphase to allow sister chromatids to come apart. The dissolution of cohesion is highly regulated; human cell lines that have defects in the regulation of cohesion show the hallmarks of cancer cells [1]. Furthermore, it has been suggested that the abnormal karyotypes that result in diseases such as Down syndrome are the result of the improper dissolution of chromosome cohesion [2]. Finally, mutation of a factor required to load cohesin—the protein complex responsible for chromosome cohesion—onto chromosomes appears to cause Cornelia de Lange syndrome, a clinically heterogeneous developmental disorder that may include facial dysmorphia, upper-extremity malformations, hirsutism, cardiac defects, growth and cognitive retardation, and gastrointestinal disorders [3,4,5]. Cohesion serves at least three roles in the cell with respect to accurate genome transmission. First, cohesion close to the centromere facilitates bi-orientation of chromosomes, such that each chromosome becomes attached to the two poles of the spindle [6]. Second, it prevents the splitting of chromosomes until all bipolar attachments are made [6]. The function of cohesion at the centromere is presumably to oppose the force of microtubules, which pull the chromosomes to opposite spindle poles; this force is not exerted along the chromosome arms, which means that cohesion at centromeres and along arms is functionally distinct. Third, cohesion along chromosome arms may be essential for proper chromosome condensation [7,8], although the function of cohesion at chromosome arms is something of a mystery. Cohesion in eukaryotic cells is mediated by a multi-subunit protein complex called cohesin. Cohesin consists of four proteins: Smc1, Smc3, Scc1/Mcd1 …