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PubMed1989

A comparative study on ethanol and acetaldehyde as inducers of chromosome malsegregation in Aspergillus nidulans.

The activity of ethyl alcohol and acetaldehyde on mitotic chromosome segregation and conidial germination in Aspergillus nidulans was studied. Ethanol effectively induced malsegregation in a narrow range of concentrations (4.5-5.5%, v/v) and was inactive at doses which arrested conidial germination (above 6%). The same bell-shaped dose-response curve was shown by the spindle poison chloral hydrate, which was active in the range 6-10 mM. Acetaldehyde displayed a diphasic dose-response curve. Genetic analysis of induced segregants suggests that the disturbance of chromosome segregation is the primary genetic effect at low doses (0.025-0.037%), while at higher doses (above 0.1%), when growth was arrested, chromosome damage was primarily induced. The same pattern of segregants was produced by hydroquinone, a substance which indirectly affects chromosome segregation in A. nidulans. These differences in the genotoxic profiles of ethanol and acetaldehyde suggest that the effect exerted by ethanol on A. nidulans mitosis is not dependent on its conversion into acetaldehyde. In the absence of an effect of ethanol on in vitro polymerization of tubulin (actively inhibited by acetaldehyde at doses above 0.075%), a direct effect of ethanol on cell membranes is hypothesized. Comparison of the inhibition of growth and the effectiveness in aneuploidy induction displayed by ethanol, methanol, n-propanol and n-butanol demonstrates, in fact, a fair correlation with logP, a descriptor of lipophilicity related to the partitioning of compounds in biological membranes.

Acetaldehyde↗
PubMed2005

Mitosis: a matter of getting rid of the right protein at the right time.

There are two major problems for the cell to solve in mitosis: how to ensure that each daughter cell receives an equal and identical complement of the genome, and how to prevent cell separation before chromosome segregation. Both these problems are solved by controlling when two specific proteins are destroyed: securin, an inhibitor of chromosome segregation, and cyclin B, which inhibits cell separation (cytokinesis). It has recently become clear that several other proteins are degraded at specific points in mitosis. This review (which is part of the Chromosome Segregation and Aneuploidy series) focuses on how specific proteins are selected for proteolysis at defined points in mitosis and how this contributes to the proper coordination of chromosome segregation and cytokinesis.

Anaphase-Promoting Complex-Cyclosome↗
PubMed1995

Fission yeast sta mutations that stabilize an unstable minichromosome are novel cdc2-interacting suppressors and are involved in regulation of spindle dynamics.

Cytological observations have shown that the presence of unstable minichromosomes can delay progression through the early stages of mitosis in fission yeast (Schizosaccharomyces pombe), suggesting that such minichromosomes may provide a useful tool for examining the system that regulates the coordinated segregation of chromosomes. One such unstable minichromosome is a large circular minichromosome. We previously showed that the mitotic instability of this minichromosome is probably due to the frequent occurrence of catenated forms of DNA after replication. To identify genes involved in the regulation of chromosome behavior in mitosis, we isolated mutants which stabilized this minichromosome. Three loci (sta1, sta2, and sta3) were identified. Two of them were found to be suppressors of temperature-sensitive mutations in cdc2, which encodes the catalytic subunit of muturation promoting factor (MPF). They show no linkage to, and are thus different from, suc1, and cdc13, previously identified as genes that interact with cdc2. The other mutation mapped to a gene previously identified as being required for the correct formation of the mitotic spindle. Data provided in this study suggest that the sta genes are involved in the regulation of spindle dynamics to ensure proper chromosome segregation during mitosis.

CDC2 Protein Kinase↗
PubMed1998

Induced chromosomal exchange directs the segregation of recombinant chromatids in mitosis of Drosophila.

In meiosis, the segregation of chromosomes at the reductional division is accomplished by first linking homologs together. Genetic exchange generates the bivalents that direct regular chromosome segregation. We show that genetic exchange in mitosis also generates bivalents and that these bivalents direct mitotic chromosome segregation. After FLP-mediated homologous recombination in G2 of the cell cycle, recombinant chromatids consistently segregate away from each other (x segregation). This pattern of segregation also applies to exchange between heterologs. Most, or all, cases of non-x segregation are the result of exchange in G1. Cytological evidence is presented that confirms the existence of the bivalents that direct this pattern of segregation. Our results implicate sister chromatid cohesion in maintenance of the bivalent. The pattern of chromatid segregation can be altered by providing an additional FRT at a more proximal site on one chromosome. We propose that sister chromatid exchange occurs at the more proximal site, allowing the recombinant chromatids to segregate together. This also allowed the recovery of reciprocal translocations following FLP-mediated heterologous recombination. The observation that exchange can generate a bivalent in mitotic divisions provides support for a simple evolutionary relationship between mitosis and meiosis.

Animals↗
PubMed2004

Cytogenetics of semi-fertile triploid and aneuploid intergeneric vine cacti hybrids.

Crosses between the diploid Hylocereus polyrhizus, as the female parent, and the tetraploid Selenicereus megalanthus, as the male parent, yielded triploid and aneuploid hybrids. The fruits of these hybrids combined the attractive appearance of Hylocereus fruits with the delicious taste of S. megalanthus fruits. The aim of this work was to assess the fertility and breeding potential of the triploid and aneuploid hybrids with a view to developing an improved vine cactus crop. Pollen mother cells at metaphase I revealed univalents, bivalents, trivalents, and occasionally quadrivalents. Chromosome distribution at anaphase I revealed different classes of chromosome segregation as well as lagging chromosomes. At metaphase II, parallel and tripolar spindles were observed. The occurrence of triads was frequent, whereas dyads were rarely observed. Pollen stainability varied among the clones studied ranging from 9.8% to 18.6%. The diameters of the stained pollen grains varied widely, probably as a result of the number of chromosomes. Despite the allotriploid origin of our hybrids, functional female and male gametes were produced in considerable proportions, most likely as a result of balanced chromosome segregation. The triploid and aneuploid clones studied yielded viable seeds whose number per fruit was strongly dependent on the pollen donor.

Breeding↗
PubMed1997

Recombinase binding specificity at the chromosome dimer resolution site dif of Escherichia coli.

Xer site-specific recombination functions in Escherichia coli chromosome segregation and cell division apparently by resolving chromosome dimers, which arise through homologous recombination, to monomers. Xer recombination requires two closely related site-specific recombinases, XerC and XerD, which bind cooperatively to the recombination site dif and catalyse separate pairs of strand exchanges. The dif site is an imperfect palindrome whose left and right halves are bound by XerC and XerD, respectively. By using variant dif sites in which the symmetry between the XerC and XerD binding sites was increased incrementally, the determinants in the dif site that specifically direct binding of XerC and XerD to their cognate sites were elucidated. The primary specificity nucleotides in the XerC and XerD binding sites were identified and their relative contributions to specificity assessed. The biological affects of these mutations on site-specific recombination, chromosome segregation and cell division were examined. The specificity determinants are confined to the non-palindromic outer ends of the binding sites. Replacement of the wild-type dif site with mutated dif sites at the normal location in the replication terminus region of the chromosome revealed that the sequence of the dif site can be altered substantially while retaining apparently normal chromosome segregation activity.

Base Sequence↗
PubMed1998

A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers.

Genetic and biochemical studies in lower eukaryotes have identified several proteins that ensure accurate segregation of chromosomes. These include the Drosophila aurora and yeast Ipl1 kinases that are required for centrosome maturation and chromosome segregation. We have identified two human homologues of these genes, termed aurora1 and aurora2, that encode cell-cycle-regulated serine/threonine kinases. Here we demonstrate that the aurora2 gene maps to chromosome 20q13, a region amplified in a variety of human cancers, including a significant number of colorectal malignancies. We propose that aurora2 may be a target of this amplicon since its DNA is amplified and its RNA overexpressed, in more than 50% of primary colorectal cancers. Furthermore, overexpression of aurora2 transforms rodent fibroblasts. These observations implicate aurora2 as a potential oncogene in many colon, breast and other solid tumors, and identify centrosome-associated proteins as novel targets for cancer therapy.

3T3 Cells↗
PubMed2004

Mitotic instability associated with late genomic changes in bone and soft tissue tumours.

One source of genomic instability in tumours is abnormal mitotic segregation of chromosomes. Evaluation of chromosome segregation and cytogenetic aberrations in 28 bone and soft tissue neoplasms revealed few mitotic disturbances in benign lesions, whereas most of the malignant tumours, except for chondrosarcomas, showed anaphase bridges and/or multipolar mitoses. Only cases with chromosomal imbalances exhibited these defects and they were not present in any of the cases with sole primary changes, indicating that mitotic instability is established relatively late in mesenchymal tumour development. Most cases with multipolar mitoses exhibited abnormal centrosome configurations. However, induction of supernumerary centrioles in vitro failed to produce mitotic abnormalities in normal cells, indicating that additional disturbances of the cell division machinery are required for the generation of mitotic multipolarity.

Adolescent↗
PubMed2003

KLP-18, a Klp2 kinesin, is required for assembly of acentrosomal meiotic spindles in Caenorhabditis elegans.

The proper segregation of chromosomes during meiosis or mitosis requires the assembly of well organized spindles. In many organisms, meiotic spindles lack centrosomes. The formation of such acentrosomal spindles seems to involve first assembly or capture of microtubules (MTs) in a random pattern around the meiotic chromosomes and then parallel bundling and bipolar organization by the action of MT motors and other proteins. Here, we describe the structure, distribution, and function of KLP-18, a Caenorhabditis elegans Klp2 kinesin. Previous reports of Klp2 kinesins agree that it concentrates in spindles, but do not provide a clear view of its function. During prometaphase, metaphase, and anaphase, KLP-18 concentrates toward the poles in both meiotic and mitotic spindles. Depletion of KLP-18 by RNA-mediated interference prevents parallel bundling/bipolar organization of the MTs that accumulate around female meiotic chromosomes. Hence, meiotic chromosome segregation fails, leading to haploid or aneuploid embryos. Subsequent assembly and function of centrosomal mitotic spindles is normal except when aberrant maternal chromatin is present. This suggests that although KLP-18 is critical for organizing chromosome-derived MTs into a parallel bipolar spindle, the order inherent in centrosome-derived astral MT arrays greatly reduces or eliminates the need for KLP-18 organizing activity in mitotic spindles.

Animals↗
PubMedDate not supplied

Comparative in vitro cytogenetic studies in mercury-exposed human lymphocytes.

As part of a long-term cytogenetic research project on mercury, we studied the in vitro clastogenic capacity of HgCl2 and CH3HgCl as well as their influence on chromosome segregation by means of a computer-aided chromosome distribution study in metaphase plates. As in other in vitro studies published elsewhere, we exposed human peripheral blood lymphocytes to different concentrations of the mercury compound during a limited period of the pre-DNA synthetic stage (G1-S) or from that stage up to mitosis (G1-M). For both exposure periods and both mercury compounds we observed a rather important clastogenic effect as well as a dissociation of the (normally highly associated) acrocentrics. The results do indicate, in conjunction with previously published data, that mercury compounds alter the chromosome segregation at lower concentrations than those observed for clastogenicity. Moreover, the effects on chromosome segregation are not necessarily due to binding to spindle proteins. Binding to--and inactivation of RNA polymerase I may for example be another mechanism of action which is more important for the inorganic form of mercury than for the organic form.

Adult↗
PubMed2003

Captivating capture: how microtubules attach to kinetochores.

Accurate chromosome segregation is essential to ensure genomic stability because the aneuploidy that results from segregation errors leads to birth defects and contributes to the development of cancer. Chromosome segregation is directed by the kinetochore, the chromosomal site of attachment to dynamic polymers called microtubules (MTs). Although the fidelity of chromosome segregation depends on precise interactions between kinetochores and MTs, it is still unclear how this interaction is mediated and regulated. Here we discuss current progress in determining how kinetochores assemble and attach to MTs during mitosis as well as how they correct errors.

Chromosome Mapping↗
PubMed2003

Distinct developmental function of two Caenorhabditis elegans homologs of the cohesin subunit Scc1/Rad21.

Cohesin, which mediates sister chromatid cohesion, is composed of four subunits, named Scc1/Rad21, Scc3, Smc1, and Smc3 in yeast. Caenorhabditis elegans has a single homolog for each of Scc3, Smc1, and Smc3, but as many as four for Scc1/Rad21 (COH-1, SCC-1/COH-2, COH-3, and REC-8). Except for REC-8 required for meiosis, function of these C. elegans proteins remains largely unknown. Herein, we examined their possible involvement in mitosis and development. Embryos depleted of the homolog of either Scc3, or Smc1, or Smc3 by RNA interference revealed a defect in mitotic chromosome segregation but not in chromosome condensation and cytokinesis. Depletion of SCC-1/COH-2 caused similar phenotypes. SCC-1/COH-2 was present in cells destined to divide. It localized to chromosomes in a cell cycle-dependent manner. Worms depleted of COH-1 arrested at either the late embryonic or the larval stage, with no indication of mitotic dysfunction. COH-1 associated chromosomes throughout the cell cycle in all somatic cells undergoing late embryogenesis or larval development. Thus, SCC-1/COH-2 and the homologs of Scc3, Smc1, and Smc3 facilitate mitotic chromosome segregation during the development, presumably by forming a cohesin complex, whereas COH-1 seems to play a role important for development but unrelated to mitosis.

Animals↗
PubMed2005

Distinct segregation dynamics of the two Vibrio cholerae chromosomes.

The study of prokaryotic chromosome segregation has focused primarily on bacteria with single circular chromosomes. Little is known about segregation in bacteria with multipartite genomes. The human diarrhoeal pathogen Vibrio cholerae has two circular chromosomes of unequal sizes. Using static and time-lapse fluorescence microscopy, we visualized the localization and segregation of the origins of replication of the V. cholerae chromosomes. In all stages of the cell cycle, the two origins localized to distinct subcellular locations. In newborn cells, the origin of chromosome I (oriCIvc) was located near the cell pole while the origin of chromosome II (oriCIIvc) was at the cell centre. Segregation of oriCIvc occurred asymmetrically from a polar position, with one duplicated origin traversing the length of the cell towards the opposite pole and the other remaining relatively fixed. In contrast, oriCIIvc segregated later in the cell cycle than oriCIvc and the two duplicated oriCIIvc regions repositioned to the new cell centres. DAPI staining of the nucleoid demonstrated that both origin regions were localized to the edge of the visible nucleoid and that oriCIvc foci were often associated with specific nucleoid substructures. The differences in localization and timing of segregation of oriCIvc and oriCIIvc suggest that distinct mechanisms govern the segregation of the two V. cholerae chromosomes.

Chromosome Segregation↗
PubMed2001

The budding yeast proteins Spc24p and Spc25p interact with Ndc80p and Nuf2p at the kinetochore and are important for kinetochore clustering and checkpoint control.

Here, we show that the budding yeast proteins Ndc80p, Nuf2p, Spc24p and Spc25p interact at the kinetochore. Consistently, Ndc80p, Nuf2p, Spc24p and Spc25p associate with centromere DNA in chromatin immunoprecipitation experiments, and SPC24 interacts genetically with MCM21 encoding a kinetochore component. Moreover, although conditional lethal spc24-2 and spc25-7 cells form a mitotic spindle, the kinetochores remain in the mother cell body and fail to segregate the chromosomes. Despite this defect in chromosome segregation, spc24-2 and spc25-7 cells do not arrest in metaphase in response to checkpoint control. Furthermore, spc24-2 cells showed a mitotic checkpoint defect when microtubules were depolymerized with nocodazole, indicating that Spc24p has a function in checkpoint control. Since Ndc80p, Nuf2p and Spc24p are conserved proteins, it is likely that similar complexes are part of the kinetochore in other organisms.

Amino Acid Sequence↗
PubMed2003

Two putative acetyltransferases, san and deco, are required for establishing sister chromatid cohesion in Drosophila.

BACKGROUND: Sister chromatid cohesion is needed for proper alignment and segregation of chromosomes during cell division. Chromatids are linked by the multiprotein cohesin complex, which binds to DNA during G(1) and then establishes cohesion during S phase DNA replication. However, many aspects of the mechanisms that establish and maintain cohesion during mitosis remain unclear. RESULTS: We found that mutations in two evolutionarily conserved Drosophila genes, san (separation anxiety) and deco (Drosophila eco1), disrupt centromeric sister chromatid cohesion very early in division. This failure of sister chromatid cohesion does not require separase and is correlated with a failure of the cohesin component Scc1 to accumulate in centromeric regions. It thus appears that these mutations interfere with the establishment of centromeric sister chromatid cohesion. Secondary consequences of these mutations include activation of the spindle checkpoint, causing metaphase delay or arrest. Some cells eventually escape the block but incur many errors in anaphase chromosome segregation. Both san and deco are predicted to encode acetyltransferases, which transfer acetyl groups either to internal lysine residues or to the N terminus of other proteins. The San protein is itself acetylated, and it associates with the Nat1 and Ard1 subunits of the NatA acetyltransferase. CONCLUSIONS: At least two diverse acetyltransferases play vital roles in regulating sister chromatid cohesion during Drosophila mitosis.

Acetyltransferases↗
PubMed2002

The unique centromeric chromatin structure of Schizosaccharomyces pombe is maintained during meiosis.

In meiosis I sister centromeres are unified in their polarity on the spindle, and this unique behavior is known to require the function of meiosis-specific factors that set some intrinsic property of the centromeres. The fission yeast, Schizosaccharomyces pombe, possesses complex centromeres consisting of repetitive DNA elements, making it an excellent model in which to study the behavior of complex centromeres. In mitosis, during which sister centromeres mediate chromosome segregation by establishing bipolar chromosome attachments to the spindle, the central core of the S. pombe centromere chromatin has a unique irregular nucleosome pattern. Deletion of repeats flanking this core structure have no effect on mitotic chromosome segregation, but have profound effects during meiosis. While this demonstrates that the outer repeats are critical for normal meiotic sister centromere behavior, exactly how they function and how monopolarity is established remains unclear. In this study we provide the first analysis of the chromatin structure of a complex centromere during meiosis. We show that the nature and extent of the unique central core chromatin structure is maintained with no measurable expansion. This demonstrates that monopolarity of sister centromeres, and subsequent reversion to bipolarity, does not involve a global change to the centromeric chromatin structure.

Centromere↗
PubMed2004

Identification of critical domains and putative partners for the Caenorhabditis elegans spindle component LIN-5.

Successful cell division requires proper assembly, placement and functioning of the spindle apparatus that segregates the chromosomes. The Caenorhabditis elegans gene lin-5 encodes a novel coiled-coil component of the spindle required for spindle positioning and chromosome segregation. To gain further insights into lin-5 function, we screened for dominant suppressors of the partial loss-of-function phenotype associated with the mutation lin-5(ev571ts ), and isolated 68 suppressing mutations. Eight out of the ten suppressors sequenced contained intragenic missense mutations immediately upstream of the lesion in lin-5(ev571ts ). These probably help to stabilize protein-protein interactions mediated by the coiled-coil domain. This domain was found to be required for binding to several putative LIN-5 interacting (LFI) proteins identified in yeast two-hybrid screens. Interestingly, interaction with the coiled-coil protein LFI-1 was specifically reduced by the lin-5(ev571ts ) mutation and restored by a representative intragenic suppressor mutation. Immunostaining experiments showed that LIN-5 and LFI-1 may co-localize around the kinetochore microtubules during metaphase, indicating potential interaction in vivo. The coiled-coil domain of LIN-5 was also found to mediate homodimerization, while the C-terminal region of LIN-5 was sufficient for interaction with GPR-1, a recently identified component of a LIN-5 spindle-regulatory complex. A single amino-acid substitution in the N-terminal region of LIN-5, encoded by the e1457 allele, abolished all LIN-5 interactions. Taken together, our results indicate that the spindle functions of LIN-5 depend on interactions with multiple protein partners, and that these interactions are mediated through several different domains of LIN-5.

Amino Acid Sequence↗
PubMed2006

Colocalization studies of Arp1 and p150Glued to spindle microtubules during mitosis: the effect of cytochalasin on the organization of microtubules and motor proteins in PtK1 cells.

Motor proteins play a fundamental role in the congression and segregation of chromosomes in mitosis as well as the formation of the mitotic spindle. In particular, the dynein/dynactin complex is involved in the maintenance of the spindle, formation of astral microtubules, chromosome motion, and chromosome segregation. Dynactin is a multisubunit, high molecular weight protein that is responsible for the attachment of cargo to dynein. There are a number of major subunits in dynactin that are presumed to be important during mitosis. Arp1 is thought to be the attachment site for cargo to the complex while p150(Glued), a side arm of this complex regulates binding to MTs and the binding of dynactin to dynein. We performed colocalization studies of Arp1 and p150(Glued) to spindle microtubules. Both Arp1 and p150(Glued) colocalize with spindle MTs as well as cytoplasmic components. When treated with cytochalasin J, Arp1 concentrates at the centrosomes and is less co-localized with spindle MTs. Cytochalasin J has less of an effect on the colocalization of p150(Glued) with spindle MTs, suggesting that Arp1 may have a cytochalasin J sensitive site.

Animals↗