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At least 595 records · Page 33Linked to original sources
PubMed2004

The ctf13-30/CTF13 genomic haploinsufficiency modifier screen identifies the yeast chromatin remodeling complex RSC, which is required for the establishment of sister chromatid cohesion.

The budding yeast centromere-kinetochore complex ensures high-fidelity chromosome segregation in mitosis and meiosis by mediating the attachment and movement of chromosomes along spindle microtubules. To identify new genes and pathways whose function impinges on chromosome transmission, we developed a genomic haploinsufficiency modifier screen and used ctf13-30, encoding a mutant core kinetochore protein, as the reference point. We demonstrate through a series of secondary screens that the genomic modifier screen is a successful method for identifying genes that encode nonessential proteins required for the fidelity of chromosome segregation. One gene isolated in our screen was RSC2, a nonessential subunit of the RSC chromatin remodeling complex. rsc2 mutants have defects in both chromosome segregation and cohesion, but the localization of kinetochore proteins to centromeres is not affected. We determined that, in the absence of RSC2, cohesin could still associate with chromosomes but fails to achieve proper cohesion between sister chromatids, indicating that RSC has a role in the establishment of cohesion. In addition, numerous subunits of RSC were affinity purified and a new component of RSC, Rtt102, was identified. Our work indicates that only a subset of the nonessential RSC subunits function in maintaining chromosome transmission fidelity.

Centromere↗
PubMed2003

A proposed role for the Polycomb group protein dRING in meiotic sister-chromatid cohesion.

ORD protein is required for accurate chromosome segregation during male and female meiosis in Drosophila melanogaster. Null ord mutations result in random segregation of sister chromatids during both meiotic divisions because cohesion is completely abolished prior to kinetochore capture of microtubules during meiosis I. Previous analyses of mutant ord alleles have led us to propose that the C-terminal half of the ORD protein mediates protein-protein interactions that are essential for sister-chromatid cohesion. To identify proteins that interact with ORD, we conducted a yeast two-hybrid screen using an ORD bait and isolated dRING, a core subunit of the Drosophila Polycomb repressive complex 1. We show that a missense mutation in ORD completely ablates the two-hybrid interaction with dRING and prevents nuclear retention of the mutant ORD protein in male meiotic cells. Using affinity-purified antibodies generated against full-length recombinant dRING, we demonstrate that dRING protein is expressed in the male and female gonads and colocalizes extensively with ORD on the chromatin of primary spermatocytes during G2 of meiosis. Our results suggest a novel role for the Polycomb group protein dRING and are consistent with the model that interaction of dRING and ORD is required to promote the proper segregation of meiotic chromosomes.

Animals↗
PubMed2006

Reinterpreting pericentromeric heterochromatin.

In fission yeast, pericentromeric heterochromatin is directly responsible for the sister chromatid cohesion that assures accurate chromosome segregation. In plants, however, heterochromatin and chromosome segregation appear to be largely unrelated: chromosome transmission is impaired by mutations in cohesion but not by mutations that affect heterochromatin formation. We argue that the formation of pericentromeric heterochromatin is primarily a response to constraints on chromosome mechanics that disfavor the transmission of recombination events in pericentromeric regions. This effect allows pericentromeres to expand to enormous sizes by the accumulation of transposons and through large-scale insertions and inversions. Although sister chromatid cohesion is spatially limited to pericentromeric regions at mitosis and meiosis II, the cohesive domains appear to be defined independently of heterochromatin. The available data from plants suggest that sister chromatid cohesion is marked by histone phosphorylation and mediated by Aurora kinases.

Cell Division↗
PubMed2005

Evolutionary dynamics of adult stem cells: comparison of random and immortal-strand segregation mechanisms.

This paper develops a point-mutation model describing the evolutionary dynamics of a population of adult stem cells. Such a model may prove useful for quantitative studies of tissue aging and the emergence of cancer. We consider two modes of chromosome segregation: (1) random segregation, where the daughter chromosomes of a given parent chromosome segregate randomly into the stem cell and its differentiating sister cell and (2) "immortal DNA strand" co-segregation, for which the stem cell retains the daughter chromosomes with the oldest parent strands. Immortal strand co-segregation is a mechanism, originally proposed by [Cairns Nature (London) 255, 197 (1975)], by which stem cells preserve the integrity of their genomes. For random segregation, we develop an ordered strand pair formulation of the dynamics, analogous to the ordered strand pair formalism developed for quasispecies dynamics involving semiconservative replication with imperfect lesion repair (in this context, lesion repair is taken to mean repair of postreplication base-pair mismatches). Interestingly, a similar formulation is possible with immortal strand co-segregation, despite the fact that this segregation mechanism is age dependent. From our model we are able to mathematically show that, when lesion repair is imperfect, then immortal strand co-segregation leads to better preservation of the stem cell lineage than random chromosome segregation. Furthermore, our model allows us to estimate the optimal lesion repair efficiency for preserving an adult stem cell population for a given period of time. For human stem cells, we obtain that mispaired bases still present after replication and cell division should be left untouched, to avoid potentially fixing a mutation in both DNA strands.

Adult↗
PubMed1996

Natural translocation of a large segment of chromosome III to chromosome I in a laboratory strain of Saccharomyces cerevisiae.

We have investigated chromosomal segregation during meiosis in a cross between two polymorphic haploid laboratory strains of Saccharomyces cerevisiae, FL100 and GRF18. These two strains have large chromosome-length polymorphisms for chromosomes I and III allowing for easy scoring of parental chromosomes after meiotic segregation. Chromosome III in the FL100 strain was 35 kb shorter than chromosome III in GRF18, while FL100 chromosome I was 40 kb larger than chromosome I in GRF18. Segregation analysis of chromosomes I and III in 50 tetrads showed an apparent association between chromosomes I and III, whereas only the original parental association of chromosomes I and III was found in the spores. By hybridization with chromosome-specific probes we have shown that the polymorphisms are due to a large translocation from chromosome III onto chromosome I in FL100. The translocated fragment is larger than 80 kb and was mapped between Ty and HML. In nine tetrads analyzed, chromosome-length polymorphisms which did not segregate according to Mendelian law were observed.

Blotting, Southern↗
PubMed1979

Radiation-induced nondisjunction.

The methodology and results of epidemiological studies of the effects of preconception diagnostic x-rays of the abdomen on chromosome segregation in humans are described. Many studies have been conducted in a number of different countries. The vast majority show the same positive, though not significant, trend to increased nondisjunction among the offspring of irradiated women. The results of the various studies, however, cannot be pooled because of differing methodologies used. A worldwide co-operative project with standardized methodology is recommended. Such a study should identify the parental origin of the nondisjunctional event before etiological factors are investigated. Abnormal chromosome segregation during mitotic division has been inducted experimentally by the in vitro exposure of human lymphocytes to a low dose of 50 R gamma irradiation. First meiotic nondisjunction has been successfully induced by whole body exposure of female mice to a low dose of radiation. Further experiments are being conducted to try to induce abnormal segregation during second meiotic division. Because of difficulties encountered in trying to estimate total gonad doses resulting from differing techniques employed by radiologists and other health personnel, no attempt has been made to estimate the doubling dose nor minimum safe dose regarding the effects of radiation on chromosome segregation in humans. The question of time-related repair of the mechanism involved in chromosome segregation is raised.

Abnormalities, Radiation-Induced↗
PubMed1996

Effects of homology, size and exchange of the meiotic segregation of model chromosomes in Saccharomyces cerevisiae.

In most eukaryotic organisms, chiasmata, the connections formed between homologous chromosomes as a consequence of crossing over, are important for ensuring that the homologues move away from each other at meiosis I. Some organisms have the capacity to partition the rare homologues that have failed to experience reciprocal recombination. The yeast Saccharomyces cerevisiae is able to correctly partition achiasmate homologues with low fidelity by a mechanism that is largely unknown. It is possible to test which parameters affect the ability of achiasmate chromosomes to segregate by constructing strains that will have three achiasmate chromosomes at the time of meiosis. The meiotic partitioning of these chromosomes can be monitored to determine which ones segregate away from each other at meiosis I. This approach was used to test the influence of homologous yeast DNA sequences, recombination intiation sites, chromosome size and crossing over on the meiotic segregation of the model chromosomes. Chromosome size had no effect on achiasmate segregation. The influence of homologous yeast sequences on the segregation of noncrossover model chromosomes was negligible. In meioses in which two of the three model chromosomes experienced a crossover, they nearly always disjoined at meiosis I.

Chromosome Mapping↗
PubMed2004

Toward a comprehensive model for induced endoreduplication.

Both the biological significance and the molecular mechanism of endoreduplication (END) have been debated for a long time by cytogeneticists and researchers into cell cycle enzymology and dynamics alike. Mainly due to the fact that a wide variety of agents have been reported as able to induce endoreduplication and the diversity of cell types where it has been described, until now no clear or unique mechanism of induction of this phenomenon, rare in animals but otherwise quite common in plants, has been proposed. DNA topoisomerase II (topo II), plays a major role in mitotic chromosome segregation after DNA replication. The classical topo II poisons act by stabilizing the enzyme in the so-called cleavable complex and result in DNA damage as well as END, while the true catalytic inhibitors, which are not cleavable-complex-stabilizers, do induce END without concomitant DNA and chromosome damage. Taking into account these observations on the induction of END by drugs that interfere with topo II, together with our recently obtained evidence that the nature of DNA plays an important role for chromosome segregation [Cortes, F., Pastor, N., Mateos, S., Dominguez, I., 2003. The nature of DNA plays a role in chromosome segregation: endoreduplication in halogen-substituted chromosomes. DNA Repair 2, 719-726.], a straightforward model is proposed in which the different mechanisms leading to induced END are considered.

Animals↗
PubMed2004

Cdc14 and condensin control the dissolution of cohesin-independent chromosome linkages at repeated DNA.

Chromosome segregation is triggered by the cleavage of cohesins by separase. Here we show that in budding yeast separation of the ribosomal DNA (rDNA) and telomeres also requires Cdc14, a protein phosphatase known for its role in mitotic exit. Cdc14 shares this role with the FEAR network, which activates Cdc14 during early anaphase, but not the mitotic exit network, which promotes Cdc14 activity during late anaphase. We further show that CDC14 is necessary and sufficient to promote condensin enrichment at the rDNA locus and to trigger rDNA segregation in a condensin-dependent manner. We propose that Cdc14 released by the FEAR network mediates the partitioning of rDNA by facilitating the localization of condensin thereto. This dual role of the FEAR network in initiating mitotic exit and promoting chromosome segregation ensures that exit from mitosis is coupled to the completion of chromosome segregation.

Adenosine Triphosphatases↗
PubMed2006

Consequences of defective tubulin folding on heterodimer levels, mitosis and spindle morphology in Saccharomyces cerevisiae.

In budding yeast, the essential roles of microtubules include segregating chromosomes and positioning the nucleus during mitosis. Defects in these functions can lead to aneuploidy and cell death. To ensure proper mitotic spindle and cytoplasmic microtubule formation, the cell must maintain appropriate stoichiometries of alpha- and beta-tubulin, the basic subunits of microtubules. The experiments described here investigate the minimal levels of tubulin heterodimers needed for mitotic function. We have found a triple-mutant strain, pac10Delta plp1Delta yap4Delta, which has only 20% of wild-type tubulin heterodimer levels due to synthesis and folding defects. The anaphase spindles in these cells are approximately 64% the length of wild-type spindles. The mutant cells are viable and accurately segregate chromosomes in mitosis, but they do have specific defects in mitosis such as abnormal nuclear positioning. The results establish that cells with 20% of wild-type levels of tubulin heterodimers can perform essential cellular functions with a short spindle, but require higher tubulin heterodimer concentrations to attain normal spindle length and prevent mitotic defects.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Mitotic segregation of viral and cellular acentric extrachromosomal molecules by chromosome tethering.

Mitotic chromosome segregation is mediated by spindle microtubules attached to centromeres. Recent studies, however, revealed that acentric DNA molecules, such as viral replicons and double minute chromosomes, can efficiently segregate into daughter cells by associating with mitotic chromosomes. Based on this similarity between viral and cellular acentric molecules, we introduced Epstein-Barr virus vectors into cells harboring double minute chromosomes and compared their mitotic behaviors. We added lac operator repeats to an Epstein-Barr virus vector, which enabled us to readily identify the transgene in cells expressing a fusion protein between the lac repressor and green fluorescent protein. Unexpectedly, we found that Epstein-Barr virus vectors integrated into the acentric double minute chromosomes, but not into normal chromosomes, in all of the six stably transfected clones examined. While transiently transfected Epstein-Barr virus vectors randomly associated with wheel-shaped prometaphase chromosome rosettes, the chimeras of double minute chromosomes and Epstein-Barr virus vectors in stably transfected clones always attached to the periphery of chromosome rosettes. These chimeric acentric molecules faithfully represented the behavior of native double minute chromosomes, providing a tool for analyzing their behavior in living cells throughout the cell cycle. Further detailed analyses, including real-time observations, revealed that double minute chromosomes appeared to be repelled from the spindle poles at the same time that they attached to the chromosome periphery, while centromeric regions were pulled poleward by the attached microtubules. Disrupting microtubule organization eliminated such peripheral localization of double minute chromosomes, but it did not affect their association with chromosomes. The results suggest a model in which double minute chromosomes, but not Epstein-Barr virus vectors, are subject to the microtubule-mediated antipolar force, while they both employ chromosome tethering strategies to increase their segregation to daughter cells.

Centromere↗
PubMed2003

Human centromere chromatin protein hMis12, essential for equal segregation, is independent of CENP-A loading pathway.

Kinetochores are the chromosomal sites for spindle interaction and play a vital role for chromosome segregation. The composition of kinetochore proteins and their cellular roles are, however, poorly understood in higher eukaryotes. We identified a novel kinetochore protein family conserved from yeast to human that is essential for equal chromosome segregation. The human homologue hMis12 of yeast spMis12/scMtw1 retains conserved sequence features and locates at the kinetochore region indistinguishable from CENP-A, a centromeric histone variant. RNA interference (RNAi) analysis of HeLa cells shows that the reduced hMis12 results in misaligned metaphase chromosomes, lagging anaphase chromosomes, and interphase micronuclei without mitotic delay, while CENP-A is located at kinetochores. Further, the metaphase spindle length is abnormally extended. Spindle checkpoint protein hMad2 temporally localizes at kinetochores at early mitotic stages after RNAi. The RNAi deficiency of CENP-A leads to a similar mitotic phenotype, but the kinetochore signals of other kinetochore proteins, hMis6 and CENP-C, are greatly diminished. RNAi for hMis6, like that of a kinetochore kinesin CENP-E, induces mitotic arrest. Kinetochore localization of hMis12 is unaffected by CENP-A RNAi, demonstrating an independent pathway of CENP-A in human kinetochores.

Amino Acid Sequence↗
PubMed2001

Induction of aneuploidy by nickel sulfate in V79 Chinese hamster cells.

The ability of nickel sulfate (NiSO(4)) to induce chromosome aneuploidy was investigated in vitro using the V79 Chinese hamster cell line. V79 cells were treated with 100-400 microM NiSO(4) for 24h, and monitored up to 72 h following treatment with a chromosome aberration assay, a micronuclei assay using antikinetochore antibodies (CREST assay) and an anaphase/telophase assay. Aneuploid cells were induced in a significant fraction of the cell population 24-48 h following treatment with nickel sulfate. The majority of these cells were hyperdiploid. In addition, nickel sulfate caused increased frequency of cells with kinetochore-positive micronuclei as well as kinetochore-negative micronuclei. Abnormal chromosome segregation such as lagging chromosomes, chromosome bridges and asymmetric segregation were also observed in more than 50% of anaphase or telophase cells following treatment with NiSO(4). The incidences of these abnormalities were dose-dependent in general, although the effects were prominent in a sublethal dose. These results indicate that NiSO(4) has the ability to induce aneuploidy in V79 cells. In addition, the results in anaphase/telophase assay suggest that the compound may have an effect on spindle apparatus, which could result in aneuploidy following abnormal chromosome segregation.

Anaphase↗
PubMed2005

A novel role for the CBF3 kinetochore-scaffold complex in regulating septin dynamics and cytokinesis.

In budding yeast, the kinetochore scaffold complex centromere binding factor 3 (CBF3) is required to form kinetochores on centromere DNA and to allow proper chromosome segregation. We have previously shown that SKP1 and SGT1 balance the assembly and turnover of CBF3 complexes, a cycle that we suggest is independent of its role in chromosome segregation (Rodrigo-Brenni, M.C., S. Thomas, D.C. Bouck, and K.B. Kaplan. 2004. Mol. Biol. Cell. 15:3366-3378). We provide evidence that this cycle contributes to a second, kinetochore-independent function of CBF3. In this study, we show that inhibiting the assembly of CBF3 causes disorganized septins and defects in cell polarity that give rise to cytokinesis failures. Specifically, we show that septin ring separation and disassembly is delayed in anaphase, suggesting that CBF3 regulates septin dynamics. Only mutations that affect the CBF3 cycle, and not mutants in outer kinetochore subunits, cause defects in septins. These results demonstrate a novel role for CBF3 in regulating cytokinesis, a role that is reminiscent of passenger proteins. Consistent with this possibility, we find that CBF3 interacts with Bir1p, the homologue of the passenger protein Survivin. Mutants in Bir1p similarly affect septin organization, leading us to propose that CBF3 and Bir1p act as passenger proteins to coordinate chromosome segregation with cytokinesis.

Anaphase↗
PubMed2000

Architecture of the Trypanosoma brucei nucleus during interphase and mitosis.

The structural basis of mitosis, spindle organisation and chromosome segregation, in the unicellular parasite Trypanosoma brucei is poorly understood. Here, using immunocytochemistry, fluorescent in situ hybridisation and electron microscopy, we provide a detailed analysis of mitosis in this parasite. We describe the organisation of the mitotic spindle during different stages of mitosis, the complex ultrastructure of kinetochores and the identification of a potential spindle-organising centre in the mitotic nucleus. We investigate the dynamics of chromosome segregation using telomeric and chromosome-specific probes. We also discuss the problems involved in chromosome segregation in the light of the fact that the T. brucei karyotype has 22 chromosomes in the apparent presence of only eight ultrastructurally defined kinetochores.

Animals↗
PubMed2006

Centromere formation: from epigenetics to self-assembly.

This review is part of the Chromosome segregation and Aneuploidy series that focuses on the importance of chromosome segregation mechanisms in maintaining genome stability. Centromeres are specialized chromosomal domains that serve as the foundation for the mitotic kinetochore, the interaction site between the chromosome and the mitotic spindle. The chromatin of centromeres is distinguished from other chromosomal loci by the unique incorporation of the centromeric histone H3 variant, centromere protein A. Here, we review the genetic and epigenetic factors that control the formation and maintenance of centromeric chromatin and propose a chromatin self-assembly model for organizing the higher-order structure of the centromere.

Animals↗
PubMed2006

Three-dimensional analysis of mitosis and cytokinesis in the binucleate parasite Giardia intestinalis.

In the binucleate parasite Giardia intestinalis, two diploid nuclei and essential cytoskeletal structures including eight flagella are duplicated and partitioned into two daughter cells during cell division. The mechanisms of mitosis and cytokinesis in the binucleate parasite Giardia are poorly resolved, yet have important implications for the maintenance of genetic heterozygosity. To articulate the mechanism of mitosis and the plane of cell division, we used three-dimensional deconvolution microscopy of each stage of mitosis to monitor the spatial relationships of conserved cytological markers to the mitotic spindles, the centromeres and the spindle poles. Using both light- and transmission electron microscopy, we determined that Giardia has a semi-open mitosis with two extranuclear spindles that access chromatin through polar openings in the nuclear membranes. In prophase, the nuclei migrate to the cell midline, followed by lateral chromosome segregation in anaphase. Taxol treatment results in lagging chromosomes and half-spindles. Our analysis supports a nuclear migration model of mitosis with lateral chromosome segregation in the left-right axis and cytokinesis along the longitudinal plane (perpendicular to the spindles), ensuring that each daughter inherits one copy of each parental nucleus with mirror image symmetry. Fluorescence in situ hybridization (FISH) to an episomal plasmid confirms that the nuclei remain separate and are inherited with mirror image symmetry.

Animals↗