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PubMed1999

Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome.

BACKGROUND: Down syndrome, or trisomy 21, is a complex genetic disease resulting from the presence of 3 copies of chromosome 21. The origin of the extra chromosome is maternal in 95% of cases and is due to the failure of normal chromosomal segregation during meiosis. Although advanced maternal age is a major risk factor for trisomy 21, most children with Down syndrome are born to mothers <30 y of age. OBJECTIVE: On the basis of evidence that abnormal folate and methyl metabolism can lead to DNA hypomethylation and abnormal chromosomal segregation, we hypothesized that the C-to-T substitution at nucleotide 677 (677C-->T) mutation of the methylenetetrahydrofolate reductase (MTHFR) gene may be a risk factor for maternal meiotic nondisjunction and Down syndrome in young mothers. DESIGN: The frequency of the MTHFR 677C-->T mutation was evaluated in 57 mothers of children with Down syndrome and in 50 age-matched control mothers. Ratios of plasma homocysteine to methionine and lymphocyte methotrexate cytotoxicity were measured as indicators of functional folate status. RESULTS: A significant increase in plasma homocysteine concentrations and lymphocyte methotrexate cytotoxicity was observed in the mothers of children with Down syndrome, consistent with abnormal folate and methyl metabolism. Mothers with the 677C-->T mutation had a 2.6-fold higher risk of having a child with Down syndrome than did mothers without the T substitution (odds ratio: 2.6; 95% CI: 1.2, 5.8; P < 0.03). CONCLUSION: The results of this initial study indicate that folate metabolism is abnormal in mothers of children with Down syndrome and that this may be explained, in part, by a mutation in the MTHFR gene.

Adult↗

PubMed1985

Use of a human X mouse hybrid cell line to detect aneuploidy induced by environmental chemicals.

A short-term assay utilizing a human/mouse monochromosomal hybrid cell line R3-5, to detect chemically induced aneuploidy in mammalian cells is described. A single human chromosome transferred into mouse cells was used as a cytogenetic marker to quantitate abnormal chromosome segregation following chemical treatment. The human chromosome present in the mouse cells can be readily identified by differential staining procedures. The frequency of cells containing 0 or 2 human chromosomes in the progeny of chemically treated monochromosomal hybrid cells provided a direct measure of aneuploidy. We tested the sensitivity of the proposed system with 3 model chemicals (colcemid, cyclophosphamide and benomyl) known to induce numerical or structural changes in chromosomes. The frequency of an abnormal segregation of the human chromosome was found to be dose dependent and consistently higher than controls. This system has the capability to detect gain as well as loss of a chromosome resulting from nondisjunction or other mechanisms leading to aneuploidy.

Aneuploidy↗

PubMed1998

Genetic interactions between mei-S332 and ord in the control of sister-chromatid cohesion.

The Drosophila mei-S332 and ord gene products are essential for proper sister-chromatid cohesion during meiosis in both males and females. We have constructed flies that contain null mutations for both genes. Double-mutant flies are viable and fertile. Therefore, the lack of an essential role for either gene in mitotic cohesion cannot be explained by compensatory activity of the two proteins during mitotic divisions. Analysis of sex chromosome segregation in the double mutant indicates that ord is epistatic to mei-S332. We demonstrate that ord is not required for MEI-S332 protein to localize to meiotic centromeres. Although overexpression of either protein in a wild-type background does not interfere with normal meiotic chromosome segregation, extra ORD+ protein in mei-S332 mutant males enhances nondisjunction at meiosis II. Our results suggest that a balance between the activity of mei-S332 and ord is required for proper regulation of meiotic cohesion and demonstrate that additional proteins must be functioning to ensure mitotic sister-chromatid cohesion.

Animals↗

PubMed2000

Mps1p regulates meiotic spindle pole body duplication in addition to having novel roles during sporulation.

Sporulation in yeast requires that a modified form of chromosome segregation be coupled to the development of a specialized cell type, a process akin to gametogenesis. Mps1p is a dual-specificity protein kinase essential for spindle pole body (SPB) duplication and required for the spindle assembly checkpoint in mitotically dividing cells. Four conditional mutant alleles of MPS1 disrupt sporulation, producing two distinct phenotypic classes. Class I alleles of mps1 prevent SPB duplication at the restrictive temperature without affecting premeiotic DNA synthesis and recombination. Class II MPS1 alleles progress through both meiotic divisions in 30-50% of the population, but the asci are incapable of forming mature spores. Although mutations in many other genes block spore wall formation, the cells produce viable haploid progeny, whereas mps1 class II spores are unable to germinate. We have used fluorescently marked chromosomes to demonstrate that mps1 mutant cells have a dramatically increased frequency of chromosome missegregation, suggesting that loss of viability is due to a defect in spindle function. Overall, our cytological data suggest that MPS1 is required for meiotic SPB duplication, chromosome segregation, and spore wall formation.

Chromosomes, Fungal↗

PubMed2004

A variant histone H3 is enriched at telomeres in Trypanosoma brucei.

Variant histones play critical roles in transcriptional activation and repression, DNA repair and chromosome segregation. We have identified HTV, a single-copy gene in Trypanosoma brucei encoding a variant form of histone H3 (H3V). H3V is present at discrete nuclear foci that shift over the course of the cell cycle and associate with the mitotic spindle, a pattern of localization reminiscent of that described previously for both mini-chromosomes and telomeres. By combining fluorescence in situ hybridization with indirect immunofluorescence, we confirmed that the H3V foci overlap with a 177-bp repetitive sequence element found predominantly in mini-chromosomes, as well as with the TTAGGG repeats that compose telomeres. Chromatin immunoprecipitation studies, however, reveal that only the telomeric repeat DNA is substantially enriched with H3V. HTV is not essential for viability, mini-chromosome segregation, telomere maintenance or transcriptional silencing at the telomere-proximal expression sites from which bloodstream-form T. brucei controls antigenic variation. We propose that H3V represents a novel class of histone H3 variant, a finding that has evolutionary implications.

Amino Acid Sequence↗

PubMed2000

DNA-replication/DNA-damage-dependent centrosome inactivation in Drosophila embryos.

During early embryogenesis of Drosophila melanogaster, mutations in the DNA-replication checkpoint lead to chromosome-segregation failures. Here we show that these segregation failures are associated with the assembly of an anastral microtubule spindle, a mitosis-specific loss of centrosome function, and dissociation of several components of the gamma-tubulin ring complex from a core centrosomal structure. The DNA-replication inhibitor aphidicolin and DNA-damaging agents trigger identical mitotic defects in wild-type embryos, indicating that centrosome inactivation is a checkpoint-independent and mitosis-specific response to damaged or incompletely replicated DNA. We propose that centrosome inactivation is part of a damage-control system that blocks chromosome segregation when replication/damage checkpoint control fails.

Animals↗

PubMed1998

AIM-1: a mammalian midbody-associated protein required for cytokinesis.

Mitosis is a highly coordinated process that assures the fidelity of chromosome segregation. Errors in this process result in aneuploidy which can lead to cell death or oncogenesis. In this paper we describe a putative mammalian protein kinase, AIM-1 (Aurora and Ipl1-like midbody-associated protein), related to Drosophila Aurora and Saccharomyces cerevisiae Ipl1, both of which are required for chromosome segregation. AIM-1 message and protein accumulate at G2/M phase. The protein localizes at the equator of central spindles during late anaphase and at the midbody during telophase and cytokinesis. Overexpression of kinase-inactive AIM-1 disrupts cleavage furrow formation without affecting nuclear division. Furthermore, cytokinesis frequently fails, resulting in cell polyploidy and subsequent cell death. These results strongly suggest that AIM-1 is required for proper progression of cytokinesis in mammalian cells.

Amino Acid Sequence↗

PubMed2000

Dissecting cellular processes using small molecules: identification of colchicine-like, taxol-like and other small molecules that perturb mitosis.

BACKGROUND: Understanding the molecular mechanisms of complex cellular processes requires unbiased means to identify and to alter conditionally gene products that function in a pathway of interest. Although random mutagenesis and screening (forward genetics) provide a useful means to this end, the complexity of the genome, long generation time and redundancy of gene function have limited their use with mammalian systems. We sought to develop an analogous process using small molecules to modulate conditionally the function of proteins. We hoped to identify simultaneously small molecules that may serve as leads for the development of therapeutically useful agents. RESULTS: We report the results of a high-throughput, phenotype-based screen for identifying cell-permeable small molecules that affect mitosis of mammalian cells. The predominant class of compounds that emerged directly alters the stability of microtubules in the mitotic spindle. Although many of these compounds show the colchicine-like property of destabilizing microtubules, one member shows the taxol-like property of stabilizing microtubules. Another class of compounds alters chromosome segregation by novel mechanisms that do not involve direct interactions with microtubules. CONCLUSIONS: The identification of structurally diverse small molecules that affect the mammalian mitotic machinery from a large library of synthetic compounds illustrates the use of chemical genetics in dissecting an essential cellular pathway. This screen identified five compounds that affect mitosis without directly targeting microtubules. Understanding the mechanism of action of these compounds, along with future screening efforts, promises to help elucidate the molecular mechanisms involved in chromosome segregation during mitosis.

Animals↗

PubMed2005

Anaphase-promoting complex-dependent proteolysis of cell cycle regulators and genomic instability of cancer cells.

Genomic instability can be found in most cancer cells. Cell proliferation is under tight control to ensure accurate DNA replication and chromosome segregation. Cyclin-dependent kinases (Cdks) and their activating subunits, the cyclins, are the driving forces of the cell division cycle. Regulation of cyclin oscillation by ubiquitin-dependent proteolysis thereby has a central role in cell cycle regulation. The anaphase-promoting complex (APC) is a specific ubiquitin ligase and is essential for chromosome segregation, exit from mitosis and a stable subsequent G1 phase allowing cell differentiation or accurate DNA replication in the following S phase. The APC is activated by the regulatory subunits Cdc20 (APC(Cdc20)) and Cdh1 (APC(Cdh1)) to target securin, mitotic cyclins and other cell cycle regulatory proteins for proteasomal degradation. This review is focused on the role of APC-dependent proteolysis in cell cycle regulation and how its deregulation may lead to genomic instability of cancer cells.

Anaphase-Promoting Complex-Cyclosome↗

PubMed2006

Dynamic filaments of the bacterial cytoskeleton.

Bacterial cells contain a variety of structural filamentous proteins necessary for the spatial regulation of cell shape, cell division, and chromosome segregation, analogous to the eukaryotic cytoskeletal proteins. The molecular mechanisms by which these proteins function are beginning to be revealed, and these proteins show numerous three-dimensional structural features and biochemical properties similar to those of eukaryotic actin and tubulin, revealing their evolutionary relationship. Recent technological advances have illuminated links between cell division and chromosome segregation, suggesting a higher complexity and organization of the bacterial cell than was previously thought.

Actins↗

PubMed1990

[Meiotic drive of t-haplotypes: segregation of chromosomes in mice with partial trisomy].

The properties of the t haplotypes, specific mutant states of the proximal region of chromosome 17 in the house mouse keep renewing interest. One such property is increased transmission of the t haplotype from heterozygous t/+ males to their offspring. By means of reciprocal translocation T (16; 17)43H, we have constructed males with tertiary trisomy 17 (+T43/++/RB7+) carrying Robertsonian translocation Rb(16.17)7Bnr. The offspring of these males was viable when sperm of +T43/++ and Rb7+ was used. The segregation patterns in the offspring of t-bearing trisomics were analysed on days 16-18 of embryonic development. It was found that in the case when the t haplotype is on the normal acrocentric (male male ++T43/+t12+/Rb7++), its presence in the gamete +t12+/++T43 does not produce meiotic drive. However, when t6 is on Rb7, meiotic drive was equal to 80%. It is concluded that the presence of a normal homolog and a t-bearing chromosome in sperm does not result in meiotic drive. Possible mechanisms of meiotic drive of the t haplotypes are discussed.

Animals↗

PubMed2006

The bifunctional FtsK protein mediates chromosome partitioning and cell division in Caulobacter.

Bacterial chromosome partitioning and cell division are tightly connected cellular processes. We show here that the Caulobacter crescentus FtsK protein localizes to the division plane, where it mediates multiple functions involved in chromosome segregation and cytokinesis. The first 258 amino acids of the N terminus are necessary and sufficient for targeting the protein to the division plane. Furthermore, the FtsK N terminus is required to either assemble or maintain FtsZ rings at the division plane. The FtsK C terminus is essential in Caulobacter and is involved in maintaining accurate chromosome partitioning. In addition, the C-terminal region of FtsK is required for the localization of the topoisomerase IV ParC subunit to the replisome to facilitate chromosomal decatenation prior to cell division. These results suggest that the interdependence between chromosome partitioning and cell division in Caulobacter is mediated, in part, by the FtsK protein.

Bacterial Proteins↗

PubMed1997

Molecular cytogenetic diagnostics in sperm.

Among other factors contributing to male infertility, chromosomal anomalies are a frequent finding. Investigating 440 males with reduced sperm counts (< 20 x 10(6)/mL) we found 19 males with chromosome abnormalities (aneuploidies and translocations). This frequency of chromosomal aberrations (4.3%) is much higher than in the normal population. We were able to investigate sperm nuclei from seven out of these 19 men with molecular cytogenetic methods. There were two carriers of Robertsonian translocations, two had a constitutional reciprocal translocation and three were XYY males. In addition, one other man with a long history of infertility and a marker chromosome 15 was included. Using fluorescence in-situ hybridization, it was possible to investigate a great number of sperm nuclei in each case. Each translocation case showed a specific mode of chromosomal segregation; confirming the dependence on chromosomes involved and the individual segregation pattern in each patient. The well known elimination of the supernumerary Y-chromosome in XYY males during meiosis was confirmed in our study. Molecular cytogenetic investigations in sperm provide a more reliable risk estimate with respect to the possible injection of chromosomally unbalanced sperm during intracytoplasmatic sperm injection and can be valuable in genetic counselling.

Adult↗

PubMed2006

Coordination between chromosome replication, segregation, and cell division in Caulobacter crescentus.

Progression through the Caulobacter crescentus cell cycle is coupled to a cellular differentiation program. The swarmer cell is replicationally quiescent, and DNA replication initiates at the swarmer-to-stalked cell transition. There is a very short delay between initiation of DNA replication and movement of one of the newly replicated origins to the opposite pole of the cell, indicating the absence of cohesion between the newly replicated origin-proximal parts of the Caulobacter chromosome. The terminus region of the chromosome becomes located at the invaginating septum in predivisional cells, and the completely replicated terminus regions stay associated with each other after chromosome replication is completed, disassociating very late in the cell cycle shortly before the final cell division event. Invagination of the cytoplasmic membrane occurs earlier than separation of the replicated terminus regions and formation of separate nucleoids, which results in trapping of a chromosome on either side of the cell division septum, indicating that there is not a nucleoid exclusion phenotype.

Caulobacter crescentus↗

PubMed2006

A family of zinc-finger proteins is required for chromosome-specific pairing and synapsis during meiosis in C. elegans.

Homologous chromosome pairing and synapsis are prerequisite for accurate chromosome segregation during meiosis. Here, we show that a family of four related C2H2 zinc-finger proteins plays a central role in these events in C. elegans. These proteins are encoded within a tandem gene cluster. In addition to the X-specific HIM-8 protein, three additional paralogs collectively mediate the behavior of the five autosomes. Each chromosome relies on a specific member of the family to pair and synapse with its homolog. These "ZIM" proteins concentrate at special regions called meiotic pairing centers on the corresponding chromosomes. These sites are dispersed along the nuclear envelope during early meiotic prophase, suggesting a role analogous to the telomere-mediated meiotic bouquet in other organisms. To gain insight into the evolution of these components, we characterized homologs in C. briggsae and C. remanei, which revealed changes in copy number of this gene family within the nematode lineage.

Amino Acid Sequence↗

PubMed2006

NoCut: cytokinesis in check.

In this issue of Cell, Norden et al. (2006) describe a new pathway, NoCut, that links the completion of chromosome segregation to the onset of cytokinesis in budding yeast. In NoCut, Aurora kinase (Ipl1) at the spindle midzone negatively regulates cytokinesis through two proteins previously identified to be involved in cell polarity, Boi1 and Boi2.

Aurora Kinases↗

PubMed1997

Examination of the Tn5 transposase overproduction phenotype in Escherichia coli and localization of a suppressor of transposase overproduction killing that is an allele of rpoH.

Tn5 transposase (Tnp) overproduction is lethal to Escherichia coli. Tnp overproduction causes cell filamentation, abnormal chromosome segregation, and an increase in anucleated cell formation. There are two simple explanations for the observed phenotype: induction of the SOS response or of the heat shock response. The data presented here show that overproduction of Tnp neither induces an SOS response nor a strong heat shock response. However, our experiments do indicate that induction of some sigma32-programmed function(s) (either due to an rpoH mutation, a deletion of dnaK, or overproduction of sigma32) suppresses Tnp overproduction killing. This effect is not due to overproduction of DnaK, DnaJ, or GroELS. In addition, Tnp but not deltall Tnp (whose overproduction does not kill the host cells) associates with the inner cell membrane, suggesting a possible correlation between cell killing and Tnp membrane association. These observations will be discussed in the context of a model proposing that Tnp overproduction titrates an essential host factor(s) involved in an early cell division step and/or chromosome segregation.

Bacterial Proteins↗

PubMed1992

Meiotic chromosome distribution in Drosophila oocytes: roles of two kinesin-related proteins.

Recent new information regarding the proteins required for proper distribution of chromosomes in meiosis has come from studies of Drosophila mutants. These studies reveal that proteins related to the microtubule motor protein, kinesin, function in meiotic chromosome segregation in Drosophila females. The two proteins identified thus far are likely to play very different roles in the process. The ncd protein is a spindle motor in meiosis but may perform a different role in the early mitotic divisions of the embryo. nod functions earlier in meiosis than ncd, prior to the meiotic divisions, and may be either chromosome or spindle associated. The identification of nod as a kinesin protein raises new questions regarding the distributive model of meiotic chromosome segregation.

Animals↗