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Results for “Chromosome Segregation”

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PubMed1974

Chromosome segregation mechanisms.

Most aspects of chromosome distribution to the daughter cells in meiosis and mitosis are now understood, at the cellular level. The most striking evidence that the proposed explanation is valid is that it correctly predicts the outcome of experiments on living cells in which the experimenter (1) can determine the distribution of any chosen chromosome to a chosen daughter cell, (2) can induce a mal-orientation, and (3) can stabilize a mal-orientation, causing non-disjunction of a chosen bivalent. Recent reviews of chromosome distribution mechanisms are also considered, in an attempt to clarify the remaining unsolved problems.

Animals↗

PubMed2004

RNA interference demonstrates a novel role for H2A.Z in chromosome segregation.

The histone variant H2A.Z plays an essential role in metazoans but its function remains to be determined. Here, we developed a new inducible RNAi strategy to elucidate the role of H2A.Z in mammalian cell lines. We show that in the absence of H2A.Z, the genome becomes highly unstable and that this instability is caused by defects in the chromosome segregation process. Analysis of H2A.Z localization reveals that in these cells it is enriched at heterochromatic foci with HP1alpha on the arms of chromosomes but not at centromeric regions. When H2A.Z is depleted, normal HP1alpha-chromatin interactions are disrupted on the chromosomal arms and, notably, also at pericentric regions. Therefore, H2A.Z controls the localization of HP1alpha. We conclude that H2A.Z is essential for the accurate transmission of chromosomes.

Base Sequence↗

PubMed1998

Mitotic centromere-associated kinesin is important for anaphase chromosome segregation.

Mitotic centromere-associated kinesin (MCAK) is recruited to the centromere at prophase and remains centromere associated until after telophase. MCAK is a homodimer that is encoded by a single gene and has no associated subunits. A motorless version of MCAK that binds centromeres but not microtubules disrupts chromosome segregation during anaphase. Antisense-induced depletion of MCAK results in the same defect. MCAK overexpression induces centromere-independent bundling and eventual loss of spindle microtubule polymer suggesting that centromere-associated bundling and/or depolymerization activity is required for anaphase. Live cell imaging indicates that MCAK may be required to coordinate the onset of sister centromere separation.

Anaphase↗

PubMed1984

Bacterial chromosome segregation: evidence for DNA gyrase involvement in decatenation.

Nucleoids isolated from a temperature-sensitive gyrB mutant of E. coli, incubated at restrictive temperatures, exhibit increased sedimentation rates and an abnormal doublet or dumbbell-shaped morphology. Shifting cells from restrictive to permissive temperature prior to nucleoid isolation leads to decreases in the percentage of doublet nucleoids and in nucleoid sedimentation rates. When nucleoids isolated from mutant cells exposed to restrictive temperature are incubated with purified gyrase, the percentage of doublet nucleoids decreases as the total number of nucleoids increases. These results, together with the demonstrated ability of gyrase to decatenate small circular DNA molecules in vitro, suggest that gyrase participates in bacterial chromosome segregation through its decatenating activity.

Chromosomes, Bacterial↗

PubMed2005

Single-particle tracking of oriC-GFP fluorescent spots during chromosome segregation in Escherichia coli.

DNA regions close to the origin of replication were visualized by the green fluorescent protein (GFP)-Lac repressor/lac operator system. The number of oriC-GFP fluorescent spots per cell and per nucleoid in batch-cultured cells corresponded to the theoretical DNA replication pattern. A similar pattern was observed in cells growing on microscope slides used for time-lapse experiments. The trajectories of 124 oriC-GFP spots were monitored by time-lapse microscopy of 31 cells at time intervals of 1, 2, and 3 min. Spot positions were determined along the short and long axis of cells. The lengthwise movement of spots was corrected for cell elongation. The step sizes of the spots showed a Gaussian distribution with a standard deviation of approximately 110 nm. Plots of the mean square displacement versus time indicated a free diffusion regime for spot movement along the long axis of the cell, with a diffusion coefficient of 4.3+/-2.6x10(-5) microm2/s. Spot movement along the short axis showed confinement in a region of the diameter of the nucleoid ( approximately 800 nm) with an effective diffusion coefficient of 2.9+/-1.7x10(-5) microm2/s. Confidence levels for the mean square displacement analysis were obtained from numerical simulations. We conclude from the analysis that within the experimental accuracy--the limits of which are indicated and discussed--there is no evidence that spot segregation requires any other mechanism than that of cell (length) growth.

Algorithms↗

PubMed2001

SMC proteins in bacteria: condensation motors for chromosome segregation?

SMC proteins are a ubiquitous protein family, present in almost all organisms so far analysed except for a few bacteria. They function in chromosome condensation, segregation, cohesion, and DNA recombination repair in eukaryotes, and can introduce positive writhe into DNA in vitro. SMC proteins and the structurally homologous MukB protein are unusual ATPases that form antiparallel dimers, with long coiled coil segments separating globular ends capable of binding DNA. Recently, SMC proteins have been shown to be essential for chromosome condensation, segregation and cell cycle progression in bacteria. Identification of a suppressor mutation for MukB in topoisomerase I in Escherichia coli suggests that SMC proteins are involved in negative DNA supercoiling in vivo, and by this means organize and compact chromosomes. A model is discussed in which bacterial SMC proteins act after an initial separation of replicated chromosome origins into the future daughter cell, separating sister chromatids by condensing replicated DNA strands within both cell halves. This would be analogous to a pulling of DNA strands into opposite cell halves by a condensation mechanism exerted at two specialised subregions in the cell.

Bacillus subtilis↗

PubMed2002

The human papillomavirus type 16 E6 oncogene induces premature mitotic chromosome segregation.

Expression of the human papillomavirus type 16 E6 and E7 oncogenes initiates and maintains abnormal cell replication, by interacting with the p53 and retinoblastoma (Rb) gene products. Subsequent changes in host cell gene expression, as a consequence of genetic instability, can result in progression to invasive carcinoma. In addition to previously described effects of these viral oncogenes on centrosome synthesis, primarily associated with the expression of E7, the results described herein demonstrate that the E6 oncogene can induce premature chromosome segregation in human cells.

Blotting, Western↗

PubMed1995

Cloning and characterization of a cellular apoptosis susceptibility gene, the human homologue to the yeast chromosome segregation gene CSE1.

We recently isolated human cDNA fragments that render MCF-7 breast cancer cells resistant to cell death caused by Pseudomonas exotoxin, Pseudomonas exotoxin-derived immunotoxins, diphtheria toxin, and tumor necrosis factor. We report here that one of these fragments is an antisense fragment of a gene homologous to the essential yeast chromosome segregation gene CSE1. Cloning and analysis of the full-length cDNA of the human CSE1 homologue, which we name CAS for cellular apoptosis susceptibility gene, reveals a protein coding region with similar length (971 amino acids for CAS, 960 amino acids for CSE1) and 59% overall protein homology to the yeast CSE1 protein. The conservation of this gene indicates it has an important function in human cells consistent with the essential role of CSE1 in yeast. CAS is highly expressed in human tumor cell lines and in human testis and fetal liver, tissues that contain actively dividing cells. Furthermore, CAS expression increases when resting human fibroblasts are induced to proliferate and decreases when they are growth-arrested. Thus, CAS appears to play an important role in both toxin and tumor necrosis factor-mediated cell death, as well as in cell proliferation.

Amino Acid Sequence↗

PubMed1996

Human DNA topoisomerases II alpha and II beta can functionally substitute for yeast TOP2 in chromosome segregation and recombination.

The ability of the human DNA topoisomerase II alpha and II beta isozymes to complement functional defects conferred by conditional top2 mutations in Saccharomyces cerevisiae has been investigated. At the restrictive temperature, top2 strains show multiple abnormalities, including an inability to complete mitotic and meiotic division owing to a defect in chromosome segregation, and hyper-recombination within the repetitive rDNA gene cluster. We show that the human topoisomerases II alpha and II beta can each support both vegetative growth and the production of viable spores in a top2-4 mutant at the restrictive temperature. Similarly, both human isozymes can rescue a strain carrying a top2 gene disruption, and suppress hyper-recombination within the rDNA gene cluster. We conclude that the human topoisomerase II alpha and II beta isozymes are functionally interchangeable with yeast topoisomerase II and suggest that any isozyme-specific roles in human cells are likely to be dependent upon factors other than inherent differences in catalytic ability between the alpha and beta isozymes.

Antigens, Neoplasm↗

PubMed1999

Hec1p, an evolutionarily conserved coiled-coil protein, modulates chromosome segregation through interaction with SMC proteins.

hsHec1p, a Homo sapiens coiled-coil-enriched protein, plays an important role in M-phase progression in mammalian cells. A Saccharomyces cerevisiae protein, identical to Tid3p/Ndc80p and here designated scHec1p, has similarities in structure and biological function to hsHec1p. Budding yeast cells deleted in the scHEC1/NDC80 allele are not viable, but this lethal phenotype can be rescued by hsHEC1 under control of the endogenous scHEC1 promoter. At the nonpermissive temperature, significant mitotic delay, chromosomal missegregation, and decreased viability were observed in yeast cells with temperature-sensitive (ts) alleles of hsHEC1. In the hshec1-113 ts mutant, we found a single-point mutation changing Trp395 to a stop codon, which resulted in the expression of a C-terminally truncated 45-kDa protein. The binding of this mutated protein, hshec1-113p, to five identified hsHec1p-associated proteins was unchanged, while its binding to human SMC1 protein and yeast Smc1p was ts. Hec1p also interacts with Smc2p, and the binding of the mutated hshec1-113p to Smc2p was not ts. Overexpression of either hsHEC1 or scHEC1 suppressed the lethal phenotype of smc1-2 and smc2-6 at nonpermissive temperatures, suggesting that the interactions between Hec1p and Smc1p and -2p are biologically significant. These results suggest that Hec1 proteins play a critical role in modulating chromosomal segregation, in part, through their interactions with SMC proteins.

Alleles↗

PubMed2004

Kinetochore targeting of fission yeast Mad and Bub proteins is essential for spindle checkpoint function but not for all chromosome segregation roles of Bub1p.

Several lines of evidence suggest that kinetochores are organizing centers for the spindle checkpoint response and the synthesis of a "wait anaphase" signal in cases of incomplete or improper kinetochore-microtubule attachment. Here we characterize Schizosaccharomyces pombe Bub3p and study the recruitment of spindle checkpoint components to kinetochores. We demonstrate by chromatin immunoprecipitation that they all interact with the central domain of centromeres, consistent with their role in monitoring kinetochore-microtubule interactions. Bub1p and Bub3p are dependent upon one another, but independent of the Mad proteins, for their kinetochore localization. We demonstrate a clear role for the highly conserved N-terminal domain of Bub1p in the robust targeting of Bub1p, Bub3p, and Mad3p to kinetochores and show that this is crucial for an efficient checkpoint response. Surprisingly, neither this domain nor kinetochore localization is required for other functions of Bub1p in chromosome segregation.

Chromosomes, Fungal↗

PubMed1986

Single base-pair mutations in centromere element III cause aberrant chromosome segregation in Saccharomyces cerevisiae.

In this paper we show that a 211-base pair segment of CEN3 DNA is sufficient to confer wild-type centromere function in the yeast Saccharomyces cerevisiae. We used site-directed mutagenesis of the 211-base pair fragment to examine the sequence-specific functional requirements of a conserved 11-base pair segment of centromere DNA, element III (5'-TGATTTATCCGAA-3'). Element III is the most highly conserved of the centromeric DNA sequences, differing by only a single adenine X thymine base pair among the four centromere DNAs sequenced thus far. All of the element III sequences contain specific cytosine X guanine base pairs, including a 5'-CCG-3' arrangement, which we targeted for single cytosine-to-thymine mutations by using sodium bisulfite. The effects of element III mutations on plasmid and chromosome segregation were determined by mitotic stability assays. Conversion of CCG to CTG completely abolished centromere function both in plasmids and in chromosome III, whereas conversion of CCG to TCG decreased plasmid and chromosome stability moderately. The other two guanine X cytosine base pairs in element III could be independently converted to adenine X thymine base pairs without affecting plasmid or chromosome stability. We concluded that while some specific nucleotides within the conserved element III sequence are essential for proper centromere function, other conserved nucleotides can be changed.

Base Composition↗

PubMed2003

Multiple myeloma with monosomy 13 developed in trisomy 13 acute myelocytic leukemia: numerical chromosome abnormality during chromosomal segregation process.

We report here an acute myelocytic leukemia (AML-M2) patient with trisomy 13 as the sole cytogenetic anomaly, who had relapse of AML with a normal karyotype and developed multiple myeloma. Fluorescence in situ hybridization analysis using the RB gene probe revealed the plasma cells of multiple myeloma (MM) to have monosomy 13 anomaly, whereas relapsed blast cells of AML carried disomy of chromosome 13. To our knowledge, this is the first case showing clonal evolution of trisomy 13 AML and monosomy 13 MM, which might be derived from the leukemic clone at relapse.

Chromosome Aberrations↗

PubMed1996

Role of CAS, a human homologue to the yeast chromosome segregation gene CSE1, in toxin and tumor necrosis factor mediated apoptosis.

We have previously isolated by expression/selection cloning plasmids containing human cDNAs that rendered MCF-7 breast cancer cells resistant to immunotoxins, Pseudomonas exotoxin (PE), and diphtheria toxin (DT) [Brinkmann et al. (1995) Mol. Med. 1, 206-216]. Here we describe that one of these resistant plasmids, which contains an antisense cDNA fragment homologous to the yeast chromosome segregation gene CSE1 [CAS; Brinkmann et al. (1995) Proc. Natl. Acad. Sci. U.S.A. 92, 10427-10431], reduces the intracellular content of the human CSE1 homologue CAS protein. CAS reduction confers resistance not only to the ADP-ribosylating toxins PE and DT, but also to tumor necrosis factor alpha and beta. The resistance was observed as reduced apoptosis. CAS antisense did not affect the cell death induced by staurosporine, cycloheximide, or etoposide. The observation that CAS antisense can interfere with apoptosis mediated by TNF and ADP-ribosylating toxins suggests that CAS may play a role in selected pathways of apoptosis.

ADP Ribose Transferases↗

PubMed2003

Histone hyperacetylation in mitosis prevents sister chromatid separation and produces chromosome segregation defects.

Posttranslational modifications of core histones contribute to driving changes in chromatin conformation and compaction. Herein, we investigated the role of histone deacetylation on the mitotic process by inhibiting histone deacetylases shortly before mitosis in human primary fibroblasts. Cells entering mitosis with hyperacetylated histones displayed altered chromatin conformation associated with decreased reactivity to the anti-Ser 10 phospho H3 antibody, increased recruitment of protein phosphatase 1-delta on mitotic chromosomes, and depletion of heterochromatin protein 1 from the centromeric heterochromatin. Inhibition of histone deacetylation before mitosis produced defective chromosome condensation and impaired mitotic progression in living cells, suggesting that improper chromosome condensation may induce mitotic checkpoint activation. In situ hybridization analysis on anaphase cells demonstrated the presence of chromatin bridges, which were caused by persisting cohesion along sister chromatid arms after centromere separation. Thus, the presence of hyperacetylated chromatin during mitosis impairs proper chromosome condensation during the pre-anaphase stages, resulting in poor sister chromatid resolution. Lagging chromosomes consisting of single or paired sisters were also induced by the presence of hyperacetylated histones, indicating that the less constrained centromeric organization associated with heterochromatin protein 1 depletion may promote the attachment of kinetochores to microtubules coming from both poles.

Acetylation↗

PubMedDate not supplied

Regulation of chromosome segregation in Escherichia coli.

Cell division is tightly coupled to DNA replication in Escherichia coli, as evidenced by the rarity of anucleate cells in steady state cultures. When DNA synthesis is arrested, cell division also comes to a halt and filamentous growth ensues, again with little formation of anucleate cells. To test the precise role of the SfiA division inhibitor during filamentous growth, we compared sfiA+ and sfiA- strains in their response to thymine starvation. More residual division was observed in the sfiA mutant culture, and autoradiographic analysis revealed that 13% of the final population consisted of cells of normal size containing no DNA compared to 0.9% in the thymine-starved sfiA+ culture. The SfiA division inhibitor is known to be synthesized massively during thymine starvation as part of the inducible SOS response. We conclude that it prevents aberrant division and formation of anucleate cells, thus assuring proper segregation when DNA synthesis is perturbed. The SfiC division inhibition mechanism, also associated with the SOS response, does not affect cell division during thymine starvation. On the other hand, an SOS-independent mechanism of division arrest clearly comes into play during thymine starvation of a sfiA sfiC mutant: although considerable aberrant division took place, the majority of the cells formed long filaments with 1 or 2 masses of DNA. Thus, E. coli assures proper chromosome segregation by two systems when DNA replication is perturbed: the rapid, efficient SfiA division inhibitor and a less stringent SOS-independent mechanism.

Cell Division↗

PubMed1986

[Chromosome segregation in mice heterozygous for Robertsonian translocations. I. The effect of mutation in chromosome 17 on the disjunction of homologs in females].

The effects of mutations on chromosome 17 upon the segregation of the metacentric and acrocentric homologues in the progeny of female mice heterozygous for Robertsonian translocations Rb(8.17) 1Iem and Rb(16.17) 7Bnr were studied. Genetic analysis indicated that the ratio of Rb to non-Rb (normal karyotype) progeny from mothers heterozygous for mutations tf, qk, t12 were not significantly different from 1:1 expected. Introduction of mutations T, Ki, Fu, t6 into the female genotype caused strong distortion of segregation and an increase in the proportion of progeny with normal karyotype (65-70%). From the data on embryonic mortality and cytogenetic observations, it is concluded that distortion of equal transmission arises before MII of meiosis. Consequently, preferential distribution of the metacentric chromosome into the polar body during the first meiotic division is relevant to the segregation distortion observed.

Animals↗

PubMed1988

Influence of postovulatory aging on chromosome segregation during the second meiotic division in mouse oocytes: a parthenogenetic analysis.

A high incidence of parthenogenetic activation was observed when postovulatory aged mouse oocytes were exposed briefly to hyaluronidase in culture medium at 18-26 h after the human chorionic gonadotropin injection for inducing superovulation. The majority of the activated oocytes extruded a second polar body and developed a single haploid pronucleus. Cytogenetic analysis of this class of parthenogenone at metaphase of the first-cleavage mitosis has clearly demonstrated that the completion of the second meiotic division in activated aged oocytes is not associated with a significant increase in the incidence of chromosome segregation errors. The increasing postovulatory age of oocytes prior to activation was observed to significantly decrease the capacity of activated oocytes to extrude the second polar body.

Animals↗