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Results for “Chromosome Segregation”

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PubMed2004

Saccharomyces cerevisiae CSM1 gene encoding a protein influencing chromosome segregation in meiosis I interacts with elements of the DNA replication complex.

We present the characteristics of the Csm1 (Spo86) protein of Saccharomyces cerevisiae that are important for meiotic division. The level of Csm1p does not change throughout the cell cycle, but this protein is absent in mature spores. Deletion of CSM1 causes incorrect spore formation and meiotic chromosome missegregation together with increased sensitivity of vegetative cells to benomyl and manganese. In a two-hybrid analysis with Csm1p as bait, we detected interactions with three members of the Mcm2-7 family of proteins involved in the initiation of DNA replication, and with Clf1p also implicated in replication. The Csm1p-Mcm3, Mcm5 and Mcm7p interactions were confirmed by co-immunoprecipitation. Three other interacting proteins, Mgs1p, Ulp2, and Plp2, participate in chromosome assembling and segregation, whereas the function of two others has not been established. Genetic experiments showed that the two-hybrid isolates MGS1, CLF1, MCM3, 5, 7 (CDC47), and YDL089w, when overexpressed, partially suppress the csm1Delta/csm1Delta sporulation defect. We propose that, besides its other functions, Csm1p may be involved in premeiotic DNA replication.

Adenosine Triphosphatases↗

PubMed2004

Drosophila DDP1, a multi-KH-domain protein, contributes to centromeric silencing and chromosome segregation.

BACKGROUND: The Drosophila melanogaster DDP1 protein is a highly evolutionarily conserved protein that is characterised by the presence of 15 tandemly organized KH domains, known for mediating high-affinity binding to single-stranded nucleic acids (RNA and ssDNA). Consistent with its molecular organization, DDP1 binds single-stranded nucleic acids with high affinity, in vitro. It was shown earlier that, in polytene chromosomes, DDP1 is found in association with chromocenter heterochromatin, suggesting a contribution to heterochromatin formation and/or maintenance. RESULTS: In this paper, the actual contribution of DDP1 to the structural and functional properties of heterochromatin was determined through the analysis of the phenotypes associated with the hypomorphic ddp1(15.1) mutation that was generated through the mobilization of a P element inserted in the second intron of ddp1. ddp1(15.1) behaves as a dominant suppressor of PEV in the variegated rearrangement In(1)w(m4) as well as in several transgenic lines showing variegated expression of a hsp70-white(+) transgene. In polytene chromosomes from homozygous ddp1(15.1) larvae, histone H3-K9 methylation and HP1 deposition at chromocentre heterochromatin are strongly reduced. Our results also show that, when the maternal contribution of DDP1 is reduced, chromosome condensation and segregation are compromised. Moreover, in a ddp1(15.1) mutant background, transmission of the nonessential Dp1187 minichromosome is reduced. CONCLUSIONS: We conclude that DDP1 contributes to the structural and functional properties of heterochromatin. These results are discussed in the context of current models for the formation and maintenance of heterochromatin; in these models, HP1 deposition depends on H3-K9 methylation that, in turn, requires the contribution of the RNAi pathway.

Animals↗

PubMed1983

Chromosome segregation into the spermatozoa of two men heterozygous for different reciprocal translocations.

Sperm chromosomes from two human males, each heterozygous for a different reciprocal translocation, were examined. Chromosomally normal sperm were found in equal numbers to those carrying the translocation in the balanced form, in both males. Alternate segregation was more common than adjacent segregation in both translocations. Male W. G. had a greater proportion of sperm containing chromosome abnormalities unrelated to the translocation than did J.S., the second made studied. J.S. however, had a greater frequency of chromosomally unbalanced sperm. The great majority of unbalanced sperm in both males was due to adjacent I segregation.

Adult↗

PubMed2002

Sex-specific differences in meiotic chromosome segregation revealed by dicentric bridge resolution in mice.

The meiotic properties of paracentric inversion heterozygotes have been well studied in insects and plants, but not in mammalian species. In essence, a single meiotic recombination event within the inverted region results in the formation of a dicentric chromatid, which usually breaks or is stretched between the two daughter nuclei during the first meiotic anaphase. Here, we provide evidence that this is not the predominant mode of exchange resolution in female mice. In sharp contrast to previous observations in other organisms, we find that attempts to segregate the dicentric chromatid frequently result not in breakage, stretching, or loss, but instead in precocious separation of the sister centromeres of at least one homolog. This often further results in intact segregation of the dicentric into one of the meiotic products, where it can persist into the first few embryonic divisions. These novel observations point to an unusual mechanism for the processing of dicentric chromosomes in mammalian oogenesis. Furthermore, this mechanism is rare or nonexistent in mammalian spermatogenesis. Thus, our results provide additional evidence of sexual dimorphism in mammalian meiotic chromosome behavior; in "stressful" situations, meiotic sister chromatid cohesion is apparently handled differently in males than in females.

Animals↗

PubMed1998

Isolation of a Schizosaccharomyces pombe rad21ts mutant that is aberrant in chromosome segregation, microtubule function, DNA repair and sensitive to hydroxyurea: possible involvement of Rad21 in ubiquitin-mediated proteolysis.

The fission yeast DNA repair gene rad21+ is essential for cell growth. To investigate the function essential for cell proliferation, we have isolated a temperature-sensitive mutant of the rad21+ gene. The mutant, rad21-K1, showed abnormal mitosis at the nonpermissive temperature. Some cells contained abnormal nuclear structures, such as condensed chromosomes with short spindles, or chromosomes stretched or unequally separated by elongating spindles. Other cells exhibited the displaced nucleus or a cut-like phenotype. Similar abnormalities were observed when the Rad21 protein was depleted from cells. We therefore concluded that Rad21 is essential for proper segregation of chromosomes. Moreover, the rad21-K1 mutant is sensitive not only to UV and gamma-ray irradiation but to thiabendazole and hydroxyurea, indicating that Rad21 plays important roles in microtubule function, DNA repair, and S phase function. The relation to the microtubule function was further confirmed by the fact that rad21+ genetically interacts with tubulin genes, nda2+ and nda3+. Finally, the growth of the rad21-K1 mutant was inhibited at the permissive temperature by introduction of another mutation in the cut9+ gene, coding for a component of the 20S cyclosome/anaphase promoting complex, which is involved in ubiquitin-mediated proteolysis. The results suggest that these diverse functions of Rad21 may be facilitated through ubiquitin-mediated proteolysis.

Cell Cycle Proteins↗

PubMed2002

Fission yeast Pds5 is required for accurate chromosome segregation and for survival after DNA damage or metaphase arrest.

Sister chromatid cohesion, which is established during the S phase of the eukaryotic cell cycle and persists until the onset of anaphase, is essential for the maintenance of genomic integrity. Cohesion requires the multi-protein complex cohesin, as well as a number of accessory proteins including Pds5/BIMD/Spo76. In the budding yeast Saccharomyces cerevisiae Pds5 is an essential protein that localises to chromosomes in a cohesin-dependent manner. Here we describe the characterisation in the fission yeast Schizosaccharomyces pombe of pds5(+), a novel, non-essential orthologue of S. cerevisiae PDS5. The S. pombe Pds5 protein was localised to punctate nuclear foci in a manner that was dependent on the Rad21 cohesin component. This, together with additional genetic evidence, points towards an involvement of S. pombe Pds5 in sister chromatid cohesion. S. pombe pds5 mutants were hypersensitive to DNA damage and to mitotic metaphase delay, but this sensitivity was apparently not due to precocious loss of sister chromatid cohesion. These cells also suffered increased spontaneous chromosome loss and meiotic defects and their viability was dependent on the spindle checkpoint protein Bub1. Thus, while S. pombe Pds5 has an important cohesin-related role, this differs significantly from that of the equivalent budding yeast protein.

Antimetabolites, Antineoplastic↗

PubMed2005

Analysis of chromosome segregation during preimplantation genetic diagnosis in both male and female translocation heterozygotes.

Individuals carrying translocations suffer from reduced fertility or spontaneous abortions and seek help in form of assisted reproductive technology (ART) and preimplantation genetic diagnosis (PGD). While most translocations are relatively easy to detect in metaphase cells, the majority of embryonic cells biopsied in the course of in vitro fertilization (IVF) procedures are in interphase. These nuclei are thus unsuitable for analysis by chromosome banding or painting using fluorescence in situ hybridization (FISH). Thus several methods have been devised to detect translocation imbalance through FISH in single cells for purpose of PGD, among them polar body chromosome painting, interphase FISH with combination of subtelomeric and centromeric probes, breakpoint spanning probes, and cell conversion. Results with PGD indicate a significant decrease in spontaneous abortions, from 81% before PGD to 13% after PGD. They also indicate very high rates of chromosome abnormalities in embryos from translocation carriers, 72% for Robertsonian translocations and 82% for reciprocal translocations. Sperm analysis was found to be a good predictor of IVF and PGD outcome, with samples with more than 60% abnormal forms indicating poor prognosis. Similarly, the predictability from first PGD cycle results for future cycles was 90%. In summary, PGD can help translocation carriers to achieve viable pregnancies, but the success of the process is conversely related to the baseline of unbalanced gametes.

Blastula↗

PubMed2006

Addiction toxin Fst has unique effects on chromosome segregation and cell division in Enterococcus faecalis and Bacillus subtilis.

The Fst toxin of the Enterococcus faecalis pAD1-encoded par addiction module functions intracellularly to kill plasmid-free segregants. Previous results had shown that Fst induction results in membrane permeabilization and cessation of macromolecular synthesis, but only after 45 min. Electron micrographs of toxin-induced cells showed no obvious membrane abnormalities but did reveal defects in nucleoid segregation and cell division, begging the question of which is the primary effect of Fst. To distinguish the possibilities, division septae and nucleoids were visualized simultaneously with fluorescent vancomycin and a variety of DNA stains. Results showed that division and segregation defects occurred in some cells within 15 min after induction. At these early time points, affected cells remained resistant to membrane-impermeant DNA stains, suggesting that loss of membrane integrity is a secondary effect caused by ongoing division and/or segregation defects. Fst-resistant mutants showed greater variability in cell length and formed multiple septal rings even in the absence of Fst. Fst induction was also toxic to Bacillus subtilis. In this species, Fst induction caused only minor division abnormalities, but all cells showed a condensation of the nucleoid, suggesting that effects on the structure of the chromosomal DNA might be paramount.

Bacillus subtilis↗

PubMed1999

Chromosome segregation: Samurai separation of Siamese sisters.

How do cells ensure that sister chromatids are precisely partitioned in mitosis? New studies on budding yeast have revealed that sister chromatid separation at anaphase requires endoproteolytic cleavage of a protein that maintains the association between sister chromatids.

Anaphase↗

PubMed1994

Cell cycle progression and chromosome segregation in mammalian cells cultured in the presence of the topoisomerase II inhibitors ICRF-187 [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane; ADR-529] and ICRF-159 (Razoxane).

Certain bis(2,6-dioxopiperazine) derivatives, which include ICRF-187 [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl]propane; ADR-529) and its racemic compound ICRF 159 (Razoxane), have been investigated as antineoplastic agents. In addition, ICRF-187 is currently under intense study as an agent to ameliorate the cardiac toxicity of anthracycline therapy. These agents have recently been identified as inhibitors of topoisomerase II. We studied the effects of ICRF-187 and ICRF-159 on the progression of cultured epithelial cells through M phase. Beginning approximately 1.5 h after drug addition, chromosome condensation was significantly inhibited. Cells entered and progressed through M phase at near normal rates, but the lack of complete chromosome separation during anaphase resulted in catastrophic effects on normal chromosome distribution. Immunolabeling with Crest autoimmune sera, which recognizes centromere proteins, and with MPM-2 monoclonal antibody, which recognizes mitotic phosphoproteins, indicated that the centromeres of the chromosomes assembled a normal metaphase array in the presence of ICRF-187 and ICRF-159. Centromere separation in anaphase was initiated normally but was not completed because the chromatid arms failed to disengage from each other. Massive chromosome bridges were formed, and the chromatin mass became trapped in the cleavage furrow leading to its unequal distribution to the daughter cells. In many cases, all the chromatin was pushed into one of the two dividing cells. It is likely that previous studies, based on flow cytometry, indicating that bis(2,6-dioxypiperazine) derivatives cause an accumulation of cells with a 4N DNA content, reflect the incomplete segregation of chromosomes in mitosis rather than a block in G2 of the cell cycle as had been proposed.

Animals↗

PubMed1980

Patterns of cell polarity and chromosome segregation in chains of sporulating Bacillus megaterium.

The asymmetry of the DNA duplex due to polynucleotide strand complementarity could be the molecular basis of cell polarity in spore-forming bacteria. To test this possibility, the relationship of DNA strand segregation to the spore location pattern in chains of sporangia was investigated in Bacillus megaterium. Spores containing one chromosomes labelled in one of the complementary strands were formed from cells that had been allowed to segregate pulse-labelled chromosomes in minimal medium at 30 degree C. A second crop of spores was then formed from cells originating from the labelled spore population. The second generation spores inherited labelled strands from the first sporepopulation by random segregation. In contrast, the patterns of spore positions in sporangial chains were non-random. Furthermore, the non-randomness of patterning was stable and was unaffected by growth temperature (15 to 37 degrees C) or by enrichment of the minimal medium used in the segregation experiments. Since the pattern of DNA strand segregation is random and the spore location pattern in chains of sporangia is non-random, the asymmetry of the DNA duplex cannot be the determinant of cell polarity.

Bacillus megaterium↗

PubMed2003

MAN1 and emerin have overlapping function(s) essential for chromosome segregation and cell division in Caenorhabditis elegans.

Emerin and MAN1 are LEM domain-containing integral membrane proteins of the vertebrate nuclear envelope. The function of MAN1 is unknown, whereas emerin is known to interact with nuclear lamins, barrier-to-autointegration factor (BAF), nesprin-1 alpha, and a transcription repressor. Mutations in emerin cause X-linked recessive Emery-Dreifuss muscular dystrophy. Emerin and MAN1 homologs are both conserved in Caenorhabditis elegans, but loss of Ce-emerin has no detectable phenotype. We therefore used C. elegans to test the hypothesis that Ce-MAN1 overlaps functionally with Ce-emerin. Supporting this model, Ce-MAN1 interacted directly with Ce-lamin and Ce-BAF in vitro and required Ce-lamin for its nuclear envelope localization. Interestingly, RNA interference-mediated removal of approximately 90% of Ce-MAN1 was lethal to approximately 15% of embryos. However, in the absence of Ce-emerin, approximately 90% reduction of Ce-MAN1 was lethal to all embryos by the 100-cell stage, with a phenotype involving repeated cycles of anaphase chromosome bridging and cytokinesis ["cell untimely torn" (cut) phenotype]. Immunostaining showed that the anaphase-bridged chromatin specifically retained a mitosis-specific phosphohistone H3 epitope and failed to recruit detectable Ce-lamin or Ce-BAF. These findings show that LEM domain proteins are essential for cell division and that Ce-emerin and Ce-MAN1 share at least one and possibly multiple overlapping functions, which may be relevant to Emery-Dreifuss muscular dystrophy.

Animals↗

PubMed1999

Defects in components of the proteasome enhance transcriptional silencing at fission yeast centromeres and impair chromosome segregation.

Fission yeast centromeres are transcriptionally silent and form a heterochromatin-like structure essential for normal centromere function; this appears analogous to heterochromatin and position effect variegation in other eukaryotes. Conditional mutations in three genes designated cep (centromere enhancer of position effect) were found to enhance transcriptional silencing within centromeres. Cloning of the cep1(+) and cep2(+) genes by functional complementation revealed that they are identical to the previously described genes pad1(+) and mts2(+), respectively, which both encode subunits of the proteasome 19S cap. Like Mts2 and Mts4, epitope-tagged Cep1/Pad1 localizes to or near the nuclear envelope throughout the cell cycle. The cep mutants display a range of phenotypes depending on the temperature. Silencing within the central domain of centromeres is increased at 36 degrees C. This suggests that the proteasome is involved in regulating silencing and thus centromeric chromatin architecture, possibly by lowering the level of some chromatin-associated protein by ubiquitin-dependent degradation. This is the first report of defective proteasome function affecting heterochromatin-mediated transcriptional silencing. At 36 and 32 degrees C, the cep mutants lose chromosomes at an elevated rate, and at 18 degrees C, the mutants are cryosensitive for growth. Cytological analysis at 18 degrees C revealed a defect in sister chromatid separation while other mitotic events occurred normally, indicating that cep mutations might interfere specifically with the degradation of inhibitor(s) of sister chromatid separation. These observations suggest that 19S subunits confer a level of substrate specificity on the proteasome and raise the possibility of a link between components involved in centromere architecture and sister chromatid cohesion.

Basic Helix-Loop-Helix Leucine Zipper Transcriptio↗

PubMed2002

Cdc37 is essential for chromosome segregation and cytokinesis in higher eukaryotes.

Cdc37 has been shown to be required for the activity and stability of protein kinases that regulate different stages of cell cycle progression. However, little is known so far regarding interactions of Cdc37 with kinases that play a role in cell division. Here we show that the loss of function of Cdc37 in Drosophila leads to defects in mitosis and male meiosis, and that these phenotypes closely resemble those brought about by the inactivation of Aurora B. We provide evidence that Aurora B interacts with and requires the Cdc37/Hsp90 complex for its stability. We conclude that the Cdc37/Hsp90 complex modulates the function of Aurora B and that most of the phenotypes brought about by the loss of Cdc37 function can be explained by the inactivation of this kinase. These observations substantiate the role of Cdc37 as an upstream regulatory element of key cell cycle kinases.

Animals↗

PubMed1999

The rough deal protein is a new kinetochore component required for accurate chromosome segregation in Drosophila.

Mutations in the rough deal (rod) gene of Drosophila greatly increase the missegregation of sister chromatids during mitosis, suggesting a role for this gene product in spindle or kinetochore function. The activity provided by rod also appears to be necessary for the recruitment of two known kinetochore components, Zw10 and cytoplasmic dynein. In this paper we describe the cloning of rough deal and an initial cytological characterization of its product. The Rod protein shares no identifiable structural motif with other known proteins, although apparent homologs exist in the genomes of nematode and man. By immunocytochemistry we show that Rod displays a dynamic intracellular staining pattern, localizing first to kinetochores in prometaphase, but moving to kinetochore microtubules at metaphase. Early in anaphase the protein is once again restricted to the kinetochores, where it persists until the end of telophase. This behavior is in all respects similar to that described for Zw10, and suggests that the proteins function together.

Amino Acid Sequence↗

PubMed2006

PIASgamma is required for faithful chromosome segregation in human cells.

BACKGROUND: The precision of the metaphase-anaphase transition ensures stable genetic inheritance. The spindle checkpoint blocks anaphase onset until the last chromosome biorients at metaphase plate, then the bonds between sister chromatids are removed and disjoined chromatids segregate to the spindle poles. But, how sister separation is triggered is not fully understood. PRINCIPAL FINDINGS: We identify PIASgamma as a human E3 sumo ligase required for timely and efficient sister chromatid separation. In cells lacking PIASgamma, normal metaphase plates form, but the spindle checkpoint is activated, leading to a prolonged metaphase block. Sister chromatids remain cohered even if cohesin is removed by depletion of hSgo1, because DNA catenations persist at centromeres. PIASgamma-depleted cells cannot properly localize Topoisomerase II at centromeres or in the cores of mitotic chromosomes, providing a functional link between PIASgamma and Topoisomerase II. CONCLUSIONS: PIASgamma directs Topoisomerase II to specific chromosome regions that require efficient removal of DNA catenations prior to anaphase. The lack of this activity activates the spindle checkpoint, protecting cells from non-disjunction. Because DNA catenations persist without PIASgamma in the absence of cohesin, removal of catenations and cohesin rings must be regulated in parallel.

Anaphase↗

PubMed2001

Conditional mutations in gamma-tubulin reveal its involvement in chromosome segregation and cytokinesis.

gamma-Tubulin is a conserved essential protein required for assembly and function of the mitotic spindle in humans and yeast. For example, human gamma-tubulin can replace the gamma-tubulin gene in Schizosaccharomyces pombe. To understand the structural/functional domains of gamma-tubulin, we performed a systematic alanine-scanning mutagenesis of human gamma-tubulin (TUBG1) and studied phenotypes of each mutant allele in S. pombe. Our screen, both in the presence and absence of the endogenous S. pombe gamma-tubulin, resulted in 11 lethal mutations and 12 cold-sensitive mutations. Based on structural mapping onto a homology model of human gamma-tubulin generated by free energy minimization, all deleterious mutations are found in residues predicted to be located on the surface, some in positions to interact with alpha- and/or beta-tubulins in the microtubule lattice. As expected, one class of tubg1 mutations has either an abnormal assembly or loss of the mitotic spindle. Surprisingly, a subset of mutants with abnormal spindles does not arrest in M phase but proceeds through anaphase followed by abnormal cytokinesis. These studies reveal that in addition to its previously appreciated role in spindle microtubule nucleation, gamma-tubulin is involved in the coordination of postmetaphase events, anaphase, and cytokinesis.

Amino Acid Sequence↗

PubMed2005

Expression of genes regulating chromosome segregation, the cell cycle and apoptosis during human preimplantation development.

BACKGROUND: Appropriate gene expression is vital for the regulation of developmental processes. Despite this fact there is a remarkable paucity of information concerning gene activity during preimplantation development. METHODS: We employed reverse transcription and real-time fluorescent PCR to quantify the expression of nine genes (BRCA1, BRCA2, ATM, TP53, RB1, MAD2, BUB1, APC and beta-actin) in oocytes and embryos. A full characterization of all genes was achieved in 42 embryos and four oocytes. The genes analysed have a variety of important cellular functions. RESULTS: Oocytes displayed relatively high levels of mRNA transcripts, while 2-3-cell embryos were seen to contain very little mRNA from any of the genes examined. Recovery of expression levels was not seen until the 4-cell stage or later, with the presumptive activation of the embryonic genome. Some genes displayed sharp increases in expression in embryos composed of 4-8 cells, but, for most, maximum expression was not achieved until the blastocyst stage. CONCLUSIONS: Our data show that it is possible to define characteristic gene expression profiles for each stage of human preimplantation development. The identification of genes active at defined preimplantation phases may provide clues to the cellular pathways utilized at specific stages of development. Expression of genes that function in DNA repair pathways indicate that DNA damage may be common at the cleavage stage. We suggest that specific patterns of gene expression may be indicative of embryo implantation potential.

Apoptosis↗