The Centromere Frontier: Minireview Kinetochore Components, Microtubule-Based Motility, and the CEN-Value Paradox

The kinetochore, an integrated nucleic acid and protein complex, directs chromosome movement during mitosis and meiosis. Chromosome segregation depends upon the coordinated assembly of kinetochore components at the centromere DNA and attachment to the bipolar array of spindle fibers emanating from microtubule-organizing centers. Both kinetochores and spindles have been the focus of recent efforts aimed at elucidating a mechanism that accounts for the exquisite fidelity of reactions involving chance encounters. While activities of a single protein (such as protein phosphorylation, DNA binding, and transcriptional activation) may be highly conserved, individual components of complex structures may not be as forgiving of evolutionary alterations. The phylogenetic distance between yeast, the first source of centromere DNA, and humans, from which kinetochore proteins were initially isolated, has precluded the development of an in vitro kinetochore assembly system. Thus, the recent isolation of kinetochore proteins and centromere DNA from homologous systems, allowing biochemical as well as genetic analyses, will contribute to understanding the multifunctional nature of the kinetochore and how it is integrated into the cell cycle circuitry. Kinetochore Proteins Human patients with the variant of scleroderma known as CREST (calcinosis, Raynaud phenomenon, esophageal dismotility, sclerodactly, and telangiectasia) produce autoantibodies that react with a number of distinct mammalian proteins (centromere proteins [CENPs] and inner centromere proteins [INCENPs]; Table 1). These antibodies have been instrumental in delineating domains within the tripartite kinetochore structure (Earnshaw and Rattner, 1989; Earnshaw and Bernat, 1991). In yeast, proteins have been purified that specifically bind centromere DNA elements (CDEs). In a tour de force of protein biochemistry, limiting centromere-binding factors (CBF3A, CBFSB, and CBFSC) have been identified that form a 240 kd tertiary complex, CBF3 (Lechner and Carbon, 1991). These proteins, which recognize yeast Table 1. Mammalian Centromere-Binding Proteins