The Making and Breaking of Sister Chromatid Cohesion

Whether these two complexes have different functions During cell division, daughter cells must receive one is currently unknown. Binding of the cohesin complex and only one copy of each and every chromosome. To to discrete chromosomal regions occurs prior to S accomplish this, a cell has to not only duplicate each phase, and the establishment of cohesion between the chromosome, but it must also recognize that the duplisister chromatids occurs at the time of DNA replication. cated products are identical, i.e., sister chromatids, and Cohesion establishment requires the Ctf7/Eco1 protein segregate them to the two daughter cells. Segregation (henceforth Ctf7) (Skibbens et al., 1999; Toth et al., 1999), itself is achieved by the bipolar spindle apparatus, which as well as several DNA-replication-related proteins (see binds each chromosome at its kinetochore and pulls below). How Ctf7 converts the prereplication, intrachrothe bound chromosomes toward one of the two spindle mosomal associations of the cohesin complex to interpoles. But what is the mechanism that identifies two chromosomal attachments is not known, but it appears chromosomes as being sister chromatids? that DNA replication is an integral part of the process. Following DNA replication, sister chromatids are Mutations in several replication-related proteins exattached to each other along their entire length, with hibit defects in sister chromatid cohesion. One such a high degree of cohesion at centromeric regions. In protein is the budding yeast Trf4, which was recently budding yeast, cohesion sites on chromosome arms identified as DNA polymerase (Pol ) (Wang et al., are usually intragenic, about 1 kb in length, spaced, on 2000). Pol belongs to the DNA polymerase family average, 10 kb apart, and tend to be AT rich. Cohesion that is involved in repair synthesis. It was therefore sugbetween sister chromatids enables the cell to maintain gested that Pol is a specialized polymerase required the identity of chromatids as sisters, and possibly align for DNA synthesis through regions of prereplication kinetochores of sister chromatids in a way that facilitates cohesin complex binding (Wang et al., 2000). In addition, binding of microtubules from opposite spindle poles. two groups have recently identified in budding yeast In addition, sister chromatid cohesion counteracts the an alternative form of replication factor C (RF-C), the pulling forces of the spindle, thereby generating tension absence of which results in cohesion defects (Hanna et across the kinetochores and signaling the formation of al., 2001; Mayer et al., 2001). The known function of RF-C stable bipolar attachments. Cells defective in sister type complexes is to load a processivity factor (e.g., chromatid cohesion exhibit a high rate of chromosome PCNA) onto the DNA. The processivity factor, named loss; the complete obliteration of cohesion results in cell from its structure as a sliding clamp, clamps the DNA death. Several yeast cohesion mutants exhibit a delay polymerase onto its template. The replicative RF-C is in the onset of anaphase (Hanna et al., 2001; Skibbens involved in switching between DNA polymerases during et al., 1999). While this could be a consequence of the lagging strand DNA synthesis. In the cohesion-related lack of tension between the two sister chromatids, it is RF-C form (henceforth RF-C), the Rfc1 subunit of also possible that cohesion contributes to the proper the replicative RF-C is replaced by the Ctf8, Ctf18, and architecture and function of the kinetochore. Dcc1 proteins (Mayer et al., 2001). Although none of Equally important to the establishment of cohesion is these three proteins are essential for viability, mutations its subsequent dissolution; both premature sister chroin any one of them lead to premature sister chromatid matid separation and the inability to separate sister separation, a high rate of chromosome loss, and cell chromatids in a timely fashion can lead to gross chromodeaths when combined with mutations in known cohesomal imbalances upon cell division. Thus, the estabsion components (Hanna et al., 2001; Mayer et al., 2001). lishment of cohesion and the regulation of its dissolution How might DNA synthesis promote sister chromatid are the essence of faithful transmission of genetic matecohesion? Although an interaction between RF-C rial from one generation to the next. Discussed here are and Pol has not been demonstrated, it is tempting recent findings regarding some of the main players in to speculate that cohesion establishment is associated this saga: the cohesin complex, the building block of with this specialized DNA polymerase (Figure 1). Acsister chromatid cohesion; separase, also known as cording to this model, once encountering a cohesin separin, a protease that cleaves one of the cohesin comcomplex-bound region (Figure 1A), the replicative DNA plex subunits to dissolve cohesion; and securin, a sepapolymerase and its sliding clamp would dissociate and