Chromatid cohesion

The equal distribution of chromosomes during mitosis is dependent on the maintenance of chromatid cohesion. This cohesion firmly tethers the sister chromatids of a replicated chromosome to one another until its two kinetochore regions, which lie on opposite sides of the centromere, acquire the proper bipolar attachment to the forming spindle. Then, shortly after the last kinetochore in the cell attaches to the spindle, all of the sister chromatids separate along their length relatively synchronously (over a 1-3 minute period). This ‘disjunction’ marks the onset of anaphase during which time the sister kinetochores and their associated chromatids move toward the opposing spindle poles. The premature separation of one or more sister chromatids usually leads to the formation of aneuploid daughter cells with unpredictable consequences to the organism (see Fitzgerald et al., 1975; Gabarron et al., 1986). The molecular mechanism(s) responsible for chromatid cohesion during mitosis remain ambiguous and are an area of active investigation (reviewed by Heck, 1997; Biggins and Murray, 1998). The current view is that unattached kinetochores regulate anaphase onset (and thus chromatid cohesion) by inhibiting the activity of anaphase promoting complexes (APCs). These large macromolecular assemblies target specific proteins for proteolysis by ubiquitinating them (reviewed by Townsley and Ruderman, 1998). In Saccharomyces cerevisiae chromatid disjunction involves the APC-mediated degradation of the Pds1 protein (Yamamoto et al., 1996), which exists in a complex with the Esp1 protein (related to the fission yeast Cut1P; Ciosk et al., 1998). When Pds1 is destroyed Esp1 is liberated, and this event somehow induces a class of ‘glue’ proteins, called cohesins (e.g. Scc1; Michaelis et al., 1997; Guacci et al., 1997), to dissociate from the chromosome. Although this pathway has been suggested to be conserved during mitosis and meiosis in all organisms, its applicability to higher eukaryotes remains to be demonstrated. In Xenopus cohesins (including the Scc1 homologue, Xrad21) dissociate from chromosomes at the onset of mitosis, and immunodepleting the cohesin complex (including Xrad21) does not lead to chromatid disjunction (Losada et al., 1998). As noted by Biggins and Murray (1998) these data imply that many vertebrate cohesin proteins are involved in maintaining the linkage of chromatids during interphase and not mitosis, i.e. that the mechanism linking chromatids during interphase involves the cohesin complex, and differs from the mechanism linking chromatids during mitosis (see also Yanagida, 1988). The separation of sister chromatids at anaphase is a complex process and there are likely other factors involved in regulating the attachment of cohesive molecules including, e.g. transient changes in Ca2+ at anaphase onset (Groigno and Whitaker, 1998) and controlled phosphorylation by mitotic kinases (see Hirano et al., 1997; Ciosk et al., 1998). In addition, cytological observations on living and fixed spermatocytes reveal that chromatid disjunction during meiosis is mediated by two mechanistically distinct processes that can be separated temporally: one that leads to the separation of chromatid arms and another that is responsible for disjoining the chromatids in the centromere region. In this article we review and discuss 2607 Journal of Cell Science 112, 2607-2613 (1999) Printed in Great Britain © The Company of Biologists Limited 1999 JCS0467