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CENP-B: a Major Human Centromere Protein Located Beneath the Kinetochore Carol A

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CENP-B: a Major Human Centromere Protein Located Beneath the Kinetochore Carol A CENP-B: A Major Human Centromere Protein Located beneath the Kinetochore Carol A. Cooke, Rebecca L. Bernat, and William C. Earnshaw Department of Cell Biology and Anatomy, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 Abstract. The family of three structurally related au- erochromatin beneath the kinetochore. This strongly toantigens CENP-A (17 kD), CENP-B (80 kD), and supports other emerging evidence that CENP-B is CENP-C (140 kD) are the best characterized compo- specifically associated with a-satellite heterochroma- Downloaded from http://rupress.org/jcb/article-pdf/110/5/1475/1059300/1475.pdf by guest on 26 September 2021 nents of the human centromere, and they have been tin. Although in certain instances CENP-B can be widely assumed to be components of the kinetochore. seen to be concentrated immediately adjacent to the Kinetochore components are currently of great interest lower surface of the kinetochore, the outer plate re- since this structure, which has long been known to be mains virtually unlabeled. Similar analysis with a hu- the site of microtubule attachment to the chromosome, man autoimmune serum that recognizes all three is now believed to be a site of force production for CENP antigens reveals an additional unsuspected fea- anaphase chromosome movement. In the present study ture of kinetochore structure. In addition to recogniz- we have mapped the distribution of CENP-B in mitotic ing antigens in the centromeric heterochromatin, the chromosomes by immunoelectron microscopy using autoantiserum recognizes a concentration of antigens two monospecific polyclonal antibodies together with a lateral to the kinetochore. This difference in staining newly developed series of ultra-small 1-nm colloidal pattern may reflect the presence of a "collar" of chro- gold probes. We were surprised to find that >95 % of matin rich in CENP-C and/or CENP-A encircling the CENP-B is distributed throughout the centromeric het- kinetochore plates. hE centromere of mitotic chromosomes serves at least saccharomyces pombe have provided 'virtually all we know three functions. (a) It provides the point of attachment about the specific DNA sequences that are required for cen- T for the spindle microtubules. (b) The regions of the tromere function. The centromere domain in S. cerevisiae is centromere lateral to the kinetochore are the last points at relatively small, corresponding to ,o125 bp of CEN DNA which the sister chromatids adhere to one another. Thus, the (reviewed in 8, 17). In vivo this CEN DNA is found in a pro- centromere is the target for the cellular signal that triggers tected chromatin structure encompassing 250 bp of DNA the separation of sister chromatids at the onset of anaphase. flanked by nuclease hypersensitive sites (4). In contrast, the (c) The mechanochemical motor responsible for the move- centromere of S. pombe is much larger, encompassing 40-100 ment of the chromatids to the spindle poles during anaphase kb of DNA (7, 19). In addition, S. pombe centromeres con- A may be located at the centromere, perhaps as a component tain large repeated sequence elements that are present in 2-15 of the kinetochore (18, 22, 27, 33). copies per centromere (7, 9, 16, 30, 31). When mitotic chromosomes are examined by thin-section The centromeric DNA organization in higher eukaryotes EM, the centromere appears as a dense region of chromatin differs significantly from that of the yeasts. Primate centro- with a single visible structural specialization, the kineto- meres contain large amounts of repetitive DNA, the most chore, at its surface (reviewed in reference 37). The kinet- widespread of which is the a-satellite family (38). ~satellite ochore has been studied by EM since the mid 1960s (6, 20, DNA is a complex superfamily of hierarchical repeated ele- 24, 37). It is composed of four layers: an inner dense plate ments whose consensus is based on a monomer of ,0171 bp that is closely apposed to the centromeric heterochromatin, (41, 43, 46). a-satellite DNA and its associated proteins are an electron-lucent ("clear") zone, an outer dense plate, and thought to be major components of the large blocks of cen- an outermost fibrous corona. (See Fig. 10 for a map of the tromere-associated constitutive heterochromatin. kinetochore.) The kinetochore plates are disk-shaped (20), The characterization of human centromere proteins has thus, the structure resembles a multilayered button on the been made possible by the fortuitous discovery that certain surface of the centromeric heterochromatin. The kinetochore patients with rheumatic diseases produce antibodies that has proven to be difficult to isolate, and relatively little is recognize centromeres (28). In a pioneering study, such a known about its protein and nucleic acid constituents. patient serum was used to map the distribution of the auto- Studies of the yeasts Saccharomyces cerevisiae and Schizo- antigens in chromosomes of the rat kangaroo by the immuno- © The Rockefeller University Press, 0021-9525/90/0511475/14 $2.00 The Journal of Cell Biology, Volume I10, May 1990 1475-1488 1475 peroxidase technique (5). The antigens were found to be re- by autoimmune serum may involve a posttranslational modification of the stricted to the kinetochore and the chromatin immediately CENP antigens. Such modifications are not typically performed in E. coli, subjacent to it. and would thus be absent from CENP-B fusion proteins. Sera from these patients recognize three polypeptides in immunobtots of chromosomal proteins from human cells lmmunoelectron Microscopy (12). These antigens, which we designated CENP-A (17 kD), Mitotic HeLa cells were shaken from tissue culture flasks and centrifuged CENP-B (80 kD), and CENP-C (14 kD), were shown by im- at 450 g for 10 s onto glass coverslips. Interphase cells were grown on the munological criteria to be structurally related (12). The coverslips and processed in situ. Cells were fixed in 4 % formaldehyde (from results of the original immunoelectron microscopy study paraformaldehyde) in D-PBS for 20 rain and then placed in 50 mM NH4Ct in D-PBS for 10 rain. They were washed twice in KB for 5 min. Subsequent have been widely interpreted to indicate that all three of the incubations in antibody (patient autoimmune serum G. S. 1:1,000 or ra- CENP antigens are components of the kinetochore. ACA-I 1:250) were diluted in KB. After 30 rain at 370C in antibody, the Given the recent interest in the role of the kinetochore in cells were washed twice in KB, placed in the appropriate biotinylated sec- chromosome movements, it is clearly important to compile ondary antibody (Vector Laboratories, Burlingame, CA) for another 30 rain at 37°C, and finally washed with KB-. For immunolabeling of swollen chro- a definitive map of the protein components of this structure. mosomes, cells were fixed, permeabilized with detergent, and incubated with Two technical advances have combined to enable us to begin first antibody in TEEN buffer. Subsequent washes and antibody incubations to map the distribution of individual centromere proteins in were performed in KB- as above. human mitotic cells. First, we have developed high-titer For immunogold labeling the cells were incubated in streptavidin or goat anti-rabbit IgG conjugated to 1 nm gold (Streptavidin Auroprobe 1; Janssen monospecific antibodies for CENP-B (14). In addition, a re- Life Sciences Products, Piscataway, NJ) diluted 1:100 in KB- for 4 h at cently developed series of ultra-small gold probes has en- room temperature or 16 h at 4°C. After washes in KB- and D-PBS, the Downloaded from http://rupress.org/jcb/article-pdf/110/5/1475/1059300/1475.pdf by guest on 26 September 2021 abled us to perform immunogold EM on chromosomal anti- cells were fixed in 2% glutaraldehyde with 0.02% tannic acid in D-PBS and gens in permeabilized cells for the first time. silver enhanced using either Intense Silver Enhancement kit (Janssen Life Our study has yielded two unexpected results. First, we Sciences Products) or the gum arabic/silver lactate method (1 I). Enhance- ment (enlargement) of gold particles with the IntenSe kit is apparently ex- have observed strong binding of the anti-CENP-B antibodies tremely cooperative. Certain grains become quite large, while many grains to the centromeric heterochromatin beneath the kinetochore, are apparently untouched, remaining undetectable. This technique was used and virtually no binding to the kinetochore itself. Second, for the images of Figs. I, 2, and 7 A. When the gum arabic/silver lactate staining of cells with autoimmune serum reveals the pres- method (11) is used, many more enhanced gold grains of more uniform size ence of a concentration of the centromere antigens in the are detected (our unpublished observations). The gum arabic/silver lactate method was used for the images of Figs. 3-6, 7, B-D, 8, and 9. chromatin that closely surrounds the kinetochore plates. This procedure yielded good preservation of the metaphase plate, al- though microtubules were difficult to visualize in the final material. Poor visualization of tubules in the electron microscope probably results from the Materials and Methods omission of OsO4 as a stain, since the method yielded excellent microtubule morphology when streptavidin:gold was replaced by streptavidin:Texas red Buffers and cells were examined by immunofluorescence. (OsO4 had to be avoided, as it removes the metallic silver deposited around the gold grains during The buffers used were: D-PBS (8.06 mM Na2HPO4 x 7H20, 1.47 mM enhancement.) KH2HPO4, 137 mM NaCI, 2.7 mM KCI, 0.68 mM CaCI2, 0.492 mM All coverslips were dehydrated through graded ethanol and embedded in MgC12); KB (10 mM Tris: HCI pH 7.7, 150 mM NaCl, 0.1% BSA, 0.1% Polybed/812. Thin (silver) sections were cut and placed on copper grids.
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