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PubMed2006

Mitotic kinases: the key to duplication, segregation, and cytokinesis errors, chromosomal instability, and oncogenesis.

Chromosomal instability (CIN) and aneuploidy are commonly observed in the vast majority of human solid tumors and in many hematological malignancies. These features are considered defining characteristics of human breast, bladder and kidney cancers since they markedly exceed a 50% aneuploidy frequency. The detection of persistent mitotic kinase over-expression, particularly the Aurora family, and centrosome amplification in precursor/pre-malignant stages, strongly implicate these molecular changes in precipitating the aneuploidy seen in many human neoplasms. Mitotic spindle checkpoint defects may also lead to aneuploid tumors. However, the sustained over-expression and activity of various members of the mitotic kinase families, including Aurora (Aur) (A, B, C), Polo-like (Plk1-4), and Nek (NIMA1-11) in diverse human tumors strongly indicate that these entities are intimately involved in the development of errors in centrosome duplication, chromosome segregation, and cytokinesis. Mitotic kinases have also been implicated in regulating the centrosome cycle, spindle checkpoint and microtubule-kinetochore attachment, spindle assembly, and chromosome condensation. These mitotic kinases are modulated by de-novo synthesis, stability factors, phosphorylation, and ubiquitin-dependent proteolysis. They, in turn, phosphorylate a myriad of centrosomal/mitotic protein substrates, and have the ability to behave as oncogenes (i.e. Aur-A, Plk-1), providing a compelling link between errors in mitosis and oncogenic processes. The recent development of selective small molecule inhibitors of Aurora kinases, in particular, will provide useful tools to ascertain more precisely their role in cancer development. Potent inhibitors of mitotic kinases, when fully developed, have the promise to be effective agents against tumor growth, and possibly, tumor prevention as well.

Aneuploidy↗
PubMed1995

Domains required for CENP-C assembly at the kinetochore.

Chromosomes segregate at mitosis along microtubules attached to the kinetochore, an organelle that assembles at the centromere. Despite major advances in defining molecular components of the yeast segregation apparatus, including discrete centromere sequences and proteins of the kinetochore, relatively little is known of corresponding elements in more complex eukaryotes. We show here that human CENP-C, a human autoantigen previously localized to the kinetochore, assembles at centromeres of divergent species, and that the specificity of this targeting is maintained by an inherent destruction mechanism that prevents the accumulation of CENP-C and toxicity of mistargeted CENP-C. The N-terminus of CENP-C is not only required for CENP-C destruction but renders unstable proteins that otherwise possess long half-lives. The conserved targeting of CENP-C is underscored by the discovery of significant homology between regions of CENP-C and Mif2, a protein of Saccharomyces cerevisiae required for the correct segregation of chromosomes. Mutations in the Mif2 homology domain of CENP-C impair the ability of CENP-C to assemble at the kinetochore. Together, these data indicate that essential elements of the chromosome segregation apparatus are conserved in eukaryotes.

Amino Acid Sequence↗
PubMed1997

Conservation of the centromere/kinetochore protein ZW10.

Mutations in the essential Drosophila melanogaster gene zw10 disrupt chromosome segregation, producing chromosomes that lag at the metaphase plate during anaphase of mitosis and both meiotic divisions. Recent evidence suggests that the product of this gene, DmZW10, acts at the kinetochore as part of a tension-sensing checkpoint at anaphase onset. DmZW10 displays an intriguing cell cycle-dependent intracellular distribution, apparently moving from the centromere/kinetochore at prometaphase to kinetochore microtubules at metaphase, and back to the centromere/kinetochore at anaphase (Williams, B.C., M. Gatti, and M.L. Goldberg. 1996. J. Cell Biol. 134:1127-1140). We have identified ZW10-related proteins from widely diverse species with divergent centromere structures, including several Drosophilids, Caenorhabditis elegans, Arabidopsis thaliana, Mus musculus, and humans. Antibodies against the human ZW10 protein display a cell cycle-dependent staining pattern in HeLa cells strikingly similar to that previously observed for DmZW10 in dividing Drosophila cells. Injections of C. elegans ZW10 antisense RNA phenocopies important aspects of the mutant phenotype in Drosophila: these include a strong decrease in brood size, suggesting defects in meiosis or germline mitosis, a high percentage of lethality among the embryos that are produced, and the appearance of chromatin bridges at anaphase. These results indicate that at least some aspects of the functional role of the ZW10 protein in ensuring proper chromosome segregation are conserved across large evolutionary distances.

Animals↗
PubMed2000

The consequences of a non-uniform tension across kinetochores: lessons from segregation of chromosomes in the permanent translocation heterozygote Oenothera.

The alternate (zigzag) configuration of the chromosome ring in oenotheras fulfills the requirement of high tension across kinetochores for stability of the configuration and the progression to anaphase. However, also semialternate configurations (two pairs of adjacent kinetochores interspaced among the zigzag) fulfill the requirement of high tension across kinetochores. If only the magnitude of tensile force acting on a kinetochore pair governs the stability of microtubule attachments, the probability of occurrence of the semialternate configurations would be higher than that of fully alternate configurations. Yet the percentage of irregularity in the zigzag configuration is surprisingly low, which means that the semialternate configurations are corrected. The only difference which distinguishes the fully alternate and the semialternate configurations with respect to the tension across kinetochores is that the tension across a kinetochore alternating with its neighbors is rather uniformly distributed over the kinetochore, while there is a gradient of the tension in the kinetochore having a non-alternating neighbor, with low tension on the side of this neighbor. Apparently, a low tension across a part of a kinetochore brings about correction of its attachment to microtubules. This hypothesis fits with the repeat subunit model of the kinetochore; apparently, each subunit can function autonomously in the tension-governed mechanisms, stabilizing its attachment and controlling the metaphase-to-anaphase transition.

Chromosome Segregation↗
PubMed2002

Recruitment of cohesin to heterochromatic regions by Swi6/HP1 in fission yeast.

Fission yeast centromeres, like those of higher eukaryotes, are composed of repeated DNA structures and associated heterochromatin protein complexes, that have a critical function in the faithful segregation of chromosomes during cell division. Cohesin protein complexes, which are essential for sister-chromatid cohesion and proper chromosome segregation, are enriched at centromeric repeats. We have identified a functional and physical link between heterochromatin and cohesin. We find that the preferential localization of cohesins at the centromeric repeats is dependent on Swi6, a conserved heterochromatin protein that is required for proper kinetochore function. Cohesin is also enriched at the mating-type heterochromatic region in a manner that depends on Swi6 and is required to preserve the genomic integrity of this locus. We provide evidence that a cohesin subunit Psc3 interacts with Swi6 and its mouse homologue HP1. These data define a conserved function of Swi6/HP1 in recruitment of cohesin to heterochromatic regions, promoting the proper segregation of chromosomes.

Animals↗
PubMed2000

Aneuploidy and cancer.

Numeric aberrations in chromosomes, referred to as aneuploidy, is commonly observed in human cancer. Whether aneuploidy is a cause or consequence of cancer has long been debated. Three lines of evidence now make a compelling case for aneuploidy being a discrete chromosome mutation event that contributes to malignant transformation and progression process. First, precise assay of chromosome aneuploidy in several primary tumors with in situ hybridization and comparative genomic hybridization techniques have revealed that specific chromosome aneusomies correlate with distinct tumor phenotypes. Second, aneuploid tumor cell lines and in vitro transformed rodent cells have been reported to display an elevated rate of chromosome instability, thereby indicating that aneuploidy is a dynamic chromosome mutation event associated with transformation of cells. Third, and most important, a number of mitotic genes regulating chromosome segregation have been found mutated in human cancer cells, implicating such mutations in induction of aneuploidy in tumors. Some of these gene mutations, possibly allowing unequal segregations of chromosomes, also cause tumorigenic transformation of cells in vitro. In this review, the recent publications investigating aneuploidy in human cancers, rate of chromosome instability in aneuploidy tumor cells, and genes implicated in regulating chromosome segregation found mutated in cancer cells are discussed.

Aneuploidy↗
PubMed2000

Live analysis of lagging chromosomes during anaphase and their effect on spindle elongation rate in fission yeast.

The fission yeast Schizosaccharomyces pombe is widely used as a model system for studies of the cell cycle and chromosome biology. To enhance these studies we have fused GFP to the chromodomain protein Swi6p, thus allowing nuclear and chromosome behaviour to be followed in living cells using time-lapse fluorescence microscopy. Like endogenous Swi6p, GFP-Swi6p localises to the nucleus and is concentrated at the heterochromatic centromeres and telomeres. The nucleus is highly dynamic during interphase: the clustered centromeres, in particular, are highly mobile. By expressing GFP-(&agr;)2-tubulin and GFP-Swi6p in the same cells we observe that the clustered centromeres move in concert with the cytoplasmic microtubules, which is likely to reflect their association with the spindle pole body. Drug treatment indicates that this movement is dependent on intact cytoplasmic microtubules. We have also used GFP-Swi6p to investigate the properties of lagging chromosomes observed in mutants with defects in chromosome segregation. Lagging chromosomes display a variety of behaviours on anaphase spindles, most surprisingly, chromosomes appear to initiate microtubule interactions and move to the poles late in anaphase B. Interestingly, in cells displaying lagging chromosomes, the rate of spindle elongation is slowed by a factor of two. This suggests that cells are able to sense the presence of a lagging chromosome and slow anaphase B in order to allow it extra time to reach the pole. However, this mechanism is not dependent on the spindle checkpoint proteins Bub1p or Dma1p, raising the possibility that a novel checkpoint mechanism operates to retard spindle elongation if lagging chromosomes are detected. An alternative model is also discussed in which single defective kinetochores on lagging chromatids are able to interact simultaneously with microtubules emanating from both poles and affect spindle dynamics by counteracting the spindle elongation force.

Anaphase↗
PubMed2003

Transcription from the perspective of the DNA: twists and bumps in the road.

Although nature's design of the DNA double helix is ingenious for the storage of information, this design creates topological problems for the processes that occur on the DNA. Cellular processes, such as transcription, replication, chromosomal segregation, and chromosomal condensation, are all complicated by the double helix. The problem is compounded in cells since the DNA is in chromatin. Topoisomerases relax positive and negative superhelical turns in DNA, and thereby topoisomerases have long been recognized as key components of the DNA replication and chromosome segregation and condensation machinery. A role for topoisomerases in the transcription process has also been noted in living cells, but only recently has such a role been recapitulated in the test tube for transcription reactions. New data are discussed that demonstrate that for in vitro transcription reactions, topoisomerases are dispensable when the template is naked DNA, but when the template is reconstituted into chromatin, topoisomerases are required for transcription to proceed efficiently.

Animals↗
PubMed1999

[Influence of aging and sex on chromosome 21 segregation in human lymphocytes].

OBJECTIVE: To determine the influence of aging and sex on the segregation of chromosome 21. METHODS: Lymphocytes were obtained from healthy donors of different ages, both sexes, and were treated with cytochalasin B. Binucleated cells were hybridized with chromosome 21 specific probe, and simultaneously, chromosome 21 loss and non-disjunction were detected. RESULTS: The coefficients of correlation between age and binucleated cells containing 4, 2 and 6 signals were -0.35(P<0.01), 0.18 and 0.38(P<0.01) respectively. The coefficients of correlation between age and nondisjunction of chromosome 21 and micronuclei were 0.56(P<0.01) and 0.70(P<0.01) respectively. CONCLUSION: There is a significant increase with age in the number of micronuclei and missegregation. Nondisjunction of chromosome 21 is much more frequent than loss in vivo and in vitro. No significant difference in nondisjunctioin between male and female was noted. Age effect is more significant in female than in male.

Adult↗
PubMed1999

[Influence of aging and sex on chromosome 21 segregation in human lymphocytes]

OBJECTIVE: To determine the influence of aging and sex on the segregation of chromosome 21. METHODS: Lymphocytes were obtained from healthy donors of different ages, both sexes, and were treated with cytochalasin B. Binucleated cells were hybridized with chromosome 21 specific probe, and simultaneously, chromosome 21 loss and non-disjunction were detected. RESULTS: The coefficients of correlation between age and binucleated cells containing 4, 2 and 6 signals were -0.35(P<0.01), 0.18 and 0.38(P<0.01) respectively. The coefficients of correlation between age and nondisjunction of chromosome 21 and micronuclei were 0.56(P<0.01) and 0.70(P<0.01) respectively. CONCLUSION: There is a significant increase with age in the number of micronuclei and missegregation. Nondisjunction of chromosome 21 is much more frequent than loss in vivo and in vitro. No significant difference in nondisjunctioin between male and female was noted. Age effect is more significant in female than in male.

Journal Article↗
PubMed1995

The effects of a ring chromosome on the meiotic segregation of other chromosomes in Saccharomyces cerevisiae.

Meiotic chromosome segregation must occur with high fidelity in order to prevent the generation of aneuploid cells. We have previously described the identification and genetic characterization of a yeast mutant with defects in meiotic sister-chromatid segregation. We attributed the phenotype in this mutant to a dominant allele, which we referred to as SID1-1. These mutants appeared to exhibit high levels of non-disjunction and precocious separation of sister-chromatids of chromosome III, as well as precocious separation of sister chromatids of chromosome VIII and a univalent artificial chromosome. We show here that the unusual meiotic behavior of chromosome III in these strains is due to the presence of a ring III chromosome, rather than a mutant gene. Additional experiments demonstrate that a ring III/rod III pair alters the meiotic segregation of a univalent artificial chromosome.

Chromosomes, Artificial, Yeast↗
PubMed2001

Functional analysis of kinetochore assembly in Caenorhabditis elegans.

In all eukaryotes, segregation of mitotic chromosomes requires their interaction with spindle microtubules. To dissect this interaction, we use live and fixed assays in the one-cell stage Caenorhabditis elegans embryo. We compare the consequences of depleting homologues of the centromeric histone CENP-A, the kinetochore structural component CENP-C, and the chromosomal passenger protein INCENP. Depletion of either CeCENP-A or CeCENP-C results in an identical "kinetochore null" phenotype, characterized by complete failure of mitotic chromosome segregation as well as failure to recruit other kinetochore components and to assemble a mechanically stable spindle. The similarity of their depletion phenotypes, combined with a requirement for CeCENP-A to localize CeCENP-C but not vice versa, suggest that a key step in kinetochore assembly is the recruitment of CENP-C by CENP-A-containing chromatin. Parallel analysis of CeINCENP-depleted embryos revealed mitotic chromosome segregation defects different from those observed in the absence of CeCENP-A/C. Defects are observed before and during anaphase, but the chromatin separates into two equivalently sized masses. Mechanically stable spindles assemble that show defects later in anaphase and telophase. Furthermore, kinetochore assembly and the recruitment of CeINCENP to chromosomes are independent. These results suggest distinct roles for the kinetochore and the chromosomal passengers in mitotic chromosome segregation.

Animals↗
PubMed2005

Aurora-B/AIM-1 kinase activity is involved in Ras-mediated cell transformation.

Aurora-B, previously known as AIM-1, is a conserved eukaryotic mitotic protein kinase. In mammals, this kinase plays an essential role in chromosomal segregation processes, including chromosome condensation, alignment, control of spindle checkpoints, chromosome segregation, and cytokinesis. Aurora-B is overexpressed in various cancer cells, suggesting that the kinase activity perturbs chromosomal segregation processes. Its forced overexpression induces chromosomal number instability and progressive tumorigenicity in rodent cells in vitro and in vivo. Nevertheless, based on focus formation in BALB/c 3T3 A31-1-1 cells, Aurora-B is not oncogenic. Here, we show that Aurora-B kinase activity augments Ras-mediated cell transformation. RNA interference with short hairpin RNA inhibits transformation by Ras and its upstream oncogene Src, but not by the downstream oncogene Raf. In addition, the inner centromere protein, which is a passenger protein associated with Aurora-B, has a similar ability to potentiate the activity of oncogenic Ras. These data indicate that elevated Aurora-B activity promotes transformation by oncogenic Ras by enhancing oncogenic signaling and by converting chromosome number-stable cells to aneuploid cells.

Aneuploidy↗
PubMed2002

Segregating sister genomes: the molecular biology of chromosome separation.

During cell division, each daughter cell inherits one copy of every chromosome. Accurate transmission of chromosomes requires that the sister DNA molecules created during DNA replication are disentangled and then pulled to opposite poles of the cell before division. Defects in chromosome segregation produce cells that are aneuploid (containing an abnormal number of chromosomes)-a situation that can have dire consequences. Aneuploidy is a leading cause of spontaneous miscarriages in humans and is also a hallmark of many human cancer cells. Recent work with yeast, Xenopus, and other model systems has provided new information about the proteins that control chromosome segregation during cell division and how the activities of these proteins are coordinated with the cell cycle.

Adenosine Triphosphatases↗
PubMed2005

Effect of the major repeat sequence on chromosome loss in Candida albicans.

The major repeat sequence (MRS) is found at least once on all but one chromosome in Candida albicans, but as yet it has no known relation to the phenotype. The MRS affects karyotypic variation by serving as a hot spot for chromosome translocation and by expanding and contracting internal repeats, thereby changing chromosome length. Thus, MRSs on different chromosomes and those on chromosome homologues can differ in size. We proposed that the MRS's unique repeat structure and, more specifically, the size of the MRS could also affect karyotypic variation by altering the frequency of mitotic nondisjunction. Subsequent analysis shows that both natural and artificially induced differences in the size of the chromosome 5 MRS can affect chromosome segregation. Strains with chromosome 5 homologues that differ in the size of the naturally occurring MRSs show a preferential loss of the homologue with the larger MRS on sorbose, indicating that a larger MRS leads to a higher risk of mitotic nondisjunction for that homologue. While deletion of an MRS has no deleterious effect on the deletion chromosome under normal growth conditions and leads to no obvious phenotype, strains that have the MRS deleted from one chromosome 5 homologue preferentially lose the homologue with the MRS remaining. This effect on chromosome segregation is the first demonstration of a phenotype associated with the MRS.

Base Sequence↗
PubMed2005

Spindle checkpoint maintenance requires Ame1 and Okp1.

Kinetochore proteins are required for high fidelity chromosome segregation and as a platform for checkpoint signaling. Ame1 is an essential component of the COMA (Ctf19, Okp1, Mcm21, Ame1) sub-complex of the central kinetochore of budding yeast. In this study, we describe the isolation and characterization of an Ame1 conditional mutant, ame1-4. ame1-4 cells exhibit chromosome segregation defects and Mad2-dependent cell cycle delay similar to okp1-5 cells. However, the viability of ame1-4 cells is markedly reduced relative to wild type and okp1-5 cells after three hours at restrictive temperature. To determine if ame1-4 cells enter anaphase with mis-segregated chromosomes, we monitored the localization of Bub3:VFP as a marker for anaphase onset. ame1-4 cells containing mis-segregated sister chromatids initially accumulate Bub3:VFP at kinetochores, indicating checkpoint activation and a metaphase arrest. Subsequently, Bub3:VFP de-localizes and cells reinitiate DNA duplication and budding without cytokinesis in the presence of un-segregated chromosomes. Overexpression of OKP1 in ame1-4 cells restores ame1-4 protein localization and a stable arrest. Based on our results, we propose that Ame1 and Okp1 are required for a sustained checkpoint arrest in the presence of mis-segregated chromosomes. Our results suggest that checkpoint response might be controlled not only at the level of activation but also via signals that ensure maintenance of the response.

Cell Cycle↗