392 0962-8924/00/$ – see front matter © 2000 Elsevier Science Ltd. All rights reserved. trends in CELL BIOLOGY (Vol. 10) September 2000 PII: S0962-8924(00)01821-3 The proper segregation of sister chromatids during cell division requires the association of the paired chromatids with the spindle apparatus via the kine- tochore complex at the centromere. The mechanics that pull chromosomes apart during the cell cycle have been the focus of many studies (for reviews, see Refs 1 and 2). Recently, interest has shifted to the vital role of sister-chromatid cohesion in regulating chromosome segregation. While DNA catenation might contribute to linking replicated chromatids, it is clear that proteins play a crucial role in attach- ing sister chromatids during the cell cycle. There has been a wellspring of information in the past two years that has elucidated many of the factors in- volved in establishing, maintaining and releasing cohesion between sister chromatids. Much of this information has come from the work on the bud- ding yeast Saccharomyces cerevisiae and has led to an elegant model for the establishment and destruc- tion of cohesion during the cell cycle (reviewed in Ref. 3). Many functionally homologous proteins are used during cell division in all eukaryotes, and it is clear that cohesion between sister chromatids is a highly conserved mechanism. Studies of a diverse range of eukaryotes reveal, however, that there are also important differences in cohesion at the cen- tromeric regions versus the chromosome arms, be- tween mitosis and meiosis, and across different species. Eukaryotic cells are capable of two types of cell di- vision: mitosis and meiosis. At anaphase of mitosis, sister chromatids completely lose cohesion and separate to opposite poles of the dividing cell (Fig. 1). By contrast, in meiosis, the chromosomes release cohesion in a sequential process (Fig. 2) at anaphase I and anaphase II. During the first stage of meiotic cell division, sister chromatids lose cohesion along the chromosome arms, but remain associated at their centromeres as they move together to the same pole (reductional division). Not until anaphase II is cohesion lost at the centromere, enabling sister chromatids to separate fully and move to opposite poles (equational divi- sion). How is the establishment of cohesion and the loss of cohesion differentially regulated in meiosis and mitosis? In yeast, the cohesin complex is used during both processes, but an alternative cohesin subunit is employed during mitosis versus mei- osis 4–6 . This is only part of the answer, however, and might not be true in all organisms. The centromere is the site of a specialized cohesion that is required for differentiating these two division cycles. Recent evidence supports the idea that the establishment, maintenance and release of cohesion are different between the centromere and the arms. Defining the boundaries of a eukaryotic centromere The centromere is an essential cis-acting region present on every chromosome in the eukaryotic cell. Acentric chromosomes segregate randomly during cell-division events and ultimately are lost. The centromere plays two important roles during cell division. First, it is the primary site for the formation of a functional kinetochore, which is a complex of proteins that binds to spindle microtubules and coordinates chromosome movement. In mitosis and meiosis II, paired sister kinetochores allow the metaphase chromosomes to develop a stable bipolar connection with the spindle poles and mediate the segregation of chromatids to opposite poles at anaphase (Fig. 1; Fig. 2, metaphase II). By contrast, in meiosis I, paired kinetochores on sister chromatids need to act coordinately and face the same pole so that both kinetochores attach to microtubules emanating from the same pole (Fig. 2, metaphase I). The second activity localized to the centromere is the establishment and maintenance of cohesion. This function is most important for keeping sister chromatids attached at anaphase I and preventing an equational division prior to meiosis II. Although these two functions are required in all eukaryotes, there is a great deal of diversity in centromere or- ganization among budding yeast, fission yeast and higher eukaryotes (for a review, see Ref. 7). Budding yeast possess small localized, sequence-dependent centromeres, whereas other eukaryotes have large centromeric domains characterized by repetitive DNAs. The simplest centromere is found on the chromo- somes of budding yeast. It consists of a 160–220 bp core region that is highly similar on each of the 16 chromosomes of the haploid set. This core contains Separation anxiety at the centromere Kimberley J. Dej and Terry L. Orr-Weaver During mitosis, replicated sister-chromatids must maintain cohesion as they attach to the mitotic spindle. At anaphase, cohesion is lost simultaneously along the entire chromosome, releasing sisters from one another and allowing them to segregate to opposite poles. During meiosis, sisters separate in a two-step process. At anaphase of meiosis I, cohesion is lost along the chromosome arms but is maintained at centromeric regions. Not until meiosis II are sister chromatids able to break the connection at the centromere and separate away from one another. Recent studies suggest that the centromere exhibits dynamics that are very different compared with those of the chromatid arms during both mitosis and meiosis. This review discusses the nature of the specialized chromatid cohesion seen at the centromere. The authors are at the Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA. E-mail: weaver@ wi.mit.edu reviews