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PubMed1984

Inherited aplastic anemia with abnormal clones in bone marrow and increased endoreduplication in peripheral lymphocytes.

Cytogenetic studies in peripheral blood and bone marrow cells from a female patient (aged 31 years) with inherited aplastic anemia and without other congenital anomalies are reported. Endoreduplication was increased in stimulated peripheral lymphocytes in several investigations. Chromosome breaks were shown to be near the control frequency, although chromatid exchange figures and dicentrics were present. Cytogenetic analysis was extended to the three children of our patient. Abnormal clones were detected in bone marrow preparations of our patient in all cytogenetic investigations. At the first examination, two of these clones were prevalent, with their karyotypes being 48,XX, +9, +16 and 46,XX,dup(1)(q24----q32),t(17;?)(p12-13;?). The prevailing karyotype after 2 years was 46,XX,t(17;?)(p12-13;?). Involvement of chromosomes #1 and #17 is discussed, taking into account data from the literature concerning several human neoplasias.

Adult↗
PubMed1996

Endoreduplication and telomeric association in a choroid plexus carcinoma.

Cytogenetic studies showed a hyperhaploid stemline, (32,XY,+1,+7,+9,+12,+13,+14,+19,+20) in a patient with choroid plexus carcinoma. Endoreduplication and doubling of the stemline to 200-400 chromosomes per cell and variation in numerical changes were also noted. Telomeric association was present in most cells. The 12p and 20q were by far the most frequently involved chromosome arms. Telomeric association is believed to have triggered further structural changes in this case since the 12p and 20q were always involved in the few structural abnormalities identified. A review of the literature suggests that hyperhaploidy may characterize choroid plexus carcinoma and hyperdiploidy choroid plexus papilloma.

Choroid Plexus Neoplasms↗
PubMed1987

Spontaneous and cyclophosphamide-induced sister-chromatid exchanges in diploid and endoreduplicated tetraploid metaphases of preimplantation mouse embryos.

Endoreduplicated tetraploid metaphases could for the first time be induced in preimplantation mouse embryos by culture in the suboptimum medium MEM. In such endomitoses sister-chromatid exchange (SCE) frequency was approximately the same during the first and the second cell cycle. However, when morulae and blastocysts were cultured in the presence of cyclophosphamide metabolites SCE frequency was increased predominantly during the second cell cycle. Compared to diploid metaphases a decreased SCE frequency was found under both conditions of endomitoses induction, which may be related to DNA-repair processes.

Animals↗
PubMed2003

"Big it up": endoreduplication and cell-size control in plants.

Cells undergoing endoreduplication replicate chromosomal DNA without intervening mitoses. The resulting larger, higher-ploidy nucleus is often associated with an increase in cell size, but the molecular basis for this correlation remains poorly understood. Recent advances in characterising various mutants and transgenic plants are beginning to unravel how this unique type of cell cycling is regulated and how it contributes to cell-size control. Both cell growth (i.e. increase in cytoplasmic macromolecular mass) and cell expansion (i.e. increase in cell volume through vacuolation) contribute independently to increases in cell size in plants. A total organ-size checkpoint may also help to coordinate cell size and cell number within an organ, and can contribute to final cell-size determination in plants.

Cell Cycle↗
PubMed1998

Tetraploidy and partial endoreduplication in a tripronuclear zygote obtained after intracytoplasmic sperm injection.

OBJECTIVE: To describe a peculiar combination of cytogenetic abnormalities in a tripronuclear zygote obtained after intracytoplasmic sperm injection (ICSI). DESIGN: Case report. SETTING: A university hospital. PATIENT(S): A couple with a 4-year history of primary infertility. Intracytoplasmic sperm injection was performed because of male factor infertility (oligoteratozoospermia). INTERVENTION(S): Ultrasound-guided transvaginal follicular aspiration. MAIN OUTCOME MEASURE(S): Chromosomal karyotype of a tripronuclear one-cell zygote. RESULT(S): Unexpectedly, a tetraploid [92,XXYY, end3, -18, end18] chromosome complement was found, indicating injection of a diploid spermatozoon carrying two Y chromosomes. The parental origin of the other abnormalities could not be determined. The missing chromosomes may be attributed either to a hypodiploid [44,YY,-18,-18] sperm cell or to a hypohaploid [22,X,-18] oocyte. The exact tetraploid count was restored by endoreduplication of two chromosomes. This event could have occurred in one and the same or in two different pronuclei. CONCLUSION(S): Cytogenetic analysis of multipronuclear zygotes appears useful for assessing the incidence of chromosomal abnormalities at the earliest stage of conception. In addition to other methods, it also may contribute to evaluation of the transmission of aberrations by spermatozoa from infertile men.

Adult↗
PubMed2002

Stable association of mitotic cyclin B/Cdc2 to replication origins prevents endoreduplication.

We show that in fission yeast the mitotic B type cyclin Cdc13/Cdc2 kinase associates with replication origins in vivo. This association is dependent on the origin recognition complex (ORC), is established as chromosomes are replicated, and is maintained during G2 and early mitosis. Cells expressing an orp2 (ORC2) allele that reduces binding of Cdc13 to replication origins are acutely prone to chromosomal reduplication. In synchronized endoreduplicating cells, following Cdc13 ablation, replication origins are coordinately licensed prior to each successive round of S phase with the same periodicity as in a normal cell cycle. Thus, ORC bound mitotic Cyclin B/Cdc2 kinase imposes the dependency of S phase on an intervening mitosis but not the temporal licensing of replication origins between each S phase.

CDC2 Protein Kinase↗
PubMed2000

Fertile pea plants regenerate from protoplasts when calluses have not undergone endoreduplication.

Large numbers of viable protoplasts were isolated and cultured from five pea genotypes. Calluses obtained (percent final plating efficiency (% FPE)=0.65-2.82% of initially plated protoplasts) exhibited great differences in proliferation and regeneration competence between and within genotypes. Flow cytometric analyses showed the occurrence of endoreduplication processes correlated with such differences, and could serve as a tool for the early prediction of plant regeneration competence from protoplasts. Fertile plants were produced only from calluses with a normal DNA level.

Journal Article↗
PubMed1998

Endoreduplication and development: rule without dividing?

Endoreduplication, a strategy to amplify nuclear DNA without cell division, is very common but poorly understood in plants. Recent findings in Drosophila provide a first picture of the molecular mechanism, which appears to be conserved between plants and animals. In Arabidopsis, the study of trichomes, leaf epidermis and hypocotyl cells sheds new light on the developmental regulation of this process, and its relation to cell expansion.

Animals↗
PubMed1998

Cell cycle arrest and DNA endoreduplication following p21Waf1/Cip1 expression.

p21Waf1/Cip1 is a major transcriptional target of p53 and has been shown to be one of the principal mediators of the p53 induced G1 cell cycle arrest. We show that in addition to the G1 block, p21Waf1/Cip1 can also contribute to a delay in G2 and expression of p21Waf1/Cip1 gives rise to cell cycle profiles essentially indistinguishable from those obtained following p53 expression. Arrest of cells in G2 likely reflects an inability to induce cyclin B1/cdc2 kinase activity in the presence of p21Waf1/Cip1, although the inefficient association of p21Waf1/Cip1 and cyclin B1 suggests that the mechanism of inhibition is indirect. Cells released from an S-phase block were not retarded in their ability to progress through S-phase by the presence of p21Waf1/Cip1, despite efficient inhibition of cyclin E, A and B1 dependent kinase activity, suggesting that p21Waf1/Cip1 is inefficient at inhibiting replicative DNA synthesis in vivo. Interestingly, significant numbers of cells released from the p21Waf1/Cip1 activated G2 block undergo endoreduplication, passing through another S-phase before undergoing mitosis. This supports a function of the mitotic kinases in both entry into mitosis, and also in preventing re-replication of DNA following S-phase and suggests a role for p21Waf1/Cip1 in coupling DNA synthesis and mitosis. Unlike p53, which induces apoptosis in these cells, extended expression of p21Waf1/Cip1 resulted in the expression of a senescent-like phenotype in these p53 null, pRB null tumor cells.

Cell Cycle↗
PubMed2000

p21Waf1/Cip1/Sdi1-induced growth arrest is associated with depletion of mitosis-control proteins and leads to abnormal mitosis and endoreduplication in recovering cells.

Induction of a cyclin-dependent kinase inhibitor p21Waf1/ Cip1/Sdi1 is an integral part of cell growth arrest associated with senescence and damage response. p21 overexpression from an inducible promoter resulted in senescence-like growth arrest in a human fibrosarcoma cell line. After release from p21-induced growth arrest, cells re-entered the cell cycle but displayed growth retardation, cell death and decreased clonogenicity. The failure to form colonies was associated with abnormal mitosis and endoreduplication in the recovering cells and was correlated with the induced level of p21 and the duration of p21 induction. p21 induction was found to inhibit the expression of multiple proteins involved in the execution and control of mitosis. p21-induced depletion of the cellular pools of mitosis-control proteins was followed by asynchronous resynthesis of such proteins after release from p21, which explains the observed mitotic abnormalities. Genetic destabilization in cells recovering from p21-induced growth arrest may conceivably play a role in carcinogenesis and tumor progression.

Autoantigens↗
PubMed2004

Inhibition of JNK reduces G2/M transit independent of p53, leading to endoreduplication, decreased proliferation, and apoptosis in breast cancer cells.

c-Jun N-terminal kinase (JNK) is activated by diverse cell stimuli, including stress, growth factors, and cytokines. Traditionally, activation of JNK by stress treatment is thought to induce cell death. However, our recent data indicate that JNK's ability to sensitize cells to apoptosis may be, in part, cell cycle dependent. Here, we show that the majority of both paclitaxel- and UV-induced apoptosis can be inhibited by the pharmacological JNK inhibitor, SP600125, in MCF-7 cells. However, inhibition of JNK does little to reverse doxorubicin-induced apoptosis in MCF-7 cells or doxorubicin- and UV-mediated death in MDA MB-231 cells. SP treatment causes G2/M arrest of three breast cancer cell lines and results in the endoreduplication (cellular DNA content >4N) of MCF-7 and MDA MB-231 cells. These effects on cell cycle and apoptosis are not significantly altered by the inhibition of p53, indicating that JNK is functioning independently of p53. Lastly, inhibition of JNK using both SP and antisense oligonucleotides targeted to JNK1 and JNK2 reduced proliferation of all three breast cancer cell lines. Taken together, these results suggest that the activation of JNK is important for the induction of apoptosis following stresses that function at different cell cycle phases, and that basal JNK activity is necessary to promote proliferation and maintain diploidy in breast cancer cells.

Anthracenes↗
PubMed2005

Genomic instability, endoreduplication, and diminished Ig class-switch recombination in B cells lacking Nbs1.

Mre11, Rad50, and Nbs1 form an evolutionarily conserved protein complex (Mre11-Rad50-Nbs1, MRN) that has been proposed to function as a DNA damage sensor. Hypomorphic mutations in Mre11 and Nbs1 result in the human ataxia-telangiectasia-like disorder and Nijmegen breakage syndrome (NBS), respectively. In contrast, complete inactivation of Mre11, Rad50, or Nbs1 leads to early embryonic lethality, suggesting that the hypomorphic mutations may fail to reveal some of the essential functions of MRN. Here, we use Cre-loxP-mediated recombination to restrict Nbs1 deletion to B lymphocytes. We find that disruption of Nbs1 results in the accumulation of high levels of spontaneous DNA damage, impaired proliferation, and chromosomal endoreduplication. Moreover, we show that Ig class-switch recombination (CSR) is diminished in Nbs1-deficient B cells. The CSR defect is B cell-intrinsic, independent of switch-region transcription, and a consequence of inefficient recombination at the DNA level. Our findings reveal that Nbs1 is critical for efficient Ig CSR and maintenance of the integrity of chromosomal structure and number.

Animals↗
PubMed2004

Analysis of the tomato fruit growth response to temperature and plant fruit load in relation to cell division, cell expansion and DNA endoreduplication.

BACKGROUND AND AIMS: To better understand the regulation of fruit growth in response to environmental factors, the effects of temperature and plant fruit load on cell number, cell size and DNA endoreduplication were analysed. METHODS: Plants were grown at 20/20 degrees C, 25/25 degrees C and 25/20 degrees C day/night temperatures, and inflorescences were pruned to two ('2F') or five ('5F') flowers. KEY RESULTS AND CONCLUSIONS: Despite a lower fruit growth rate at 20/20 degrees C, temperature did not affect final fruit size because of the compensation between cell number and size. The higher cell number at 20/20 degrees C (9.0 x 10(6) against 7.9 x 10(6) at 25/25 degrees C and 7.7 x 10(6) at 25/20 degrees C) resulted from an extended period of cell division, and the smaller cell size was due to a shorter period of expansion rather than a lower expansion rate. By contrast, the lower fruit growth rate and size of 5F fruits compared with 2F fruits resulted from the slow down of cell expansion, whereas the number of cells was hardly affected in the proximal fruit. However, within the inflorescence the decreasing gradient of fruit size from proximal to distal fruits was due to a decrease in cell number with similar cell size. Fruit size variations within each treatment were always positively correlated to variations in cell number, but not in cell size. Negative correlations between cell size and cell number suggested that cells of tomato pericarp can be seen as a population of competing sinks. Mean ploidy was slightly delayed and reduced in 5F fruits compared with 2F fruits. It was highest at 25/25 degrees C and lowest at 25/20 degrees C. Treatments did not affect ploidy and cell size in similar ways, but within each treatment, positive correlations existed between mean ploidy and cell size, though significant only in the 2F-25/20 treatment.

Carbon↗
PubMed2002

Control of proliferation, endoreduplication and differentiation by the Arabidopsis E2Fa-DPa transcription factor.

New plant cells arise at the meristems, where they divide a few times before they leave the cell-cycle program and start to differentiate. Here we show that the E2Fa-DPa transcription factor of Arabidopsis thaliana is a key regulator determining the proliferative status of plant cells. Ectopic expression of E2Fa induced sustained cell proliferation in normally differentiated cotyledon and hypocotyl cells. The phenotype was enhanced strongly by the co-expression of E2Fa with its dimerization partner, DPa. In endoreduplicating cells, E2Fa--DPa also caused extra DNA replication that was correlated with transcriptional induction of S phase genes. Because E2Fa--DPa transgenic plants arrested early in development, we argue that controlled exit of the cell cycle is a prerequisite for normal plant development.

Arabidopsis↗
PubMed2006

Topoisomerase II inhibition and high yield of endoreduplication induced by the flavonoids luteolin and quercetin.

Luteolin and quercetin are widely distributed plant flavonoids that possess a variety of chemical and biological activities, including free-radical scavenging and antioxidant activity. Recently, both flavonoids have been reported to inhibit DNA topoisomerases I and II (topo I and topo II), a property that, together with their ability to induce DNA and chromosome damage, has made them candidate anticancer compounds. In the present study, we confirmed that both compounds are topo II inhibitors by conducting a comparative study of their effect on topo II activity from Chinese hamster ovary AA8 cells. Because interference with the function of topo II to resolve DNA entanglement at the end of replication results in chromosome malsegregation at mitosis, we investigated whether luteolin and quercetin are effective in inducing endoreduplication in AA8 cells. Concentrations of luteolin and quercetin that inhibited topo II catalytic activity resulted in extraordinarily high yields of metaphases showing diplochromosomes. Given the established relationship of polyploidy with tumor development via aneuploidy and genetic instability, these results question the usefulness of luteolin and quercetin in cancer therapy.

Animals↗
PubMed2026

Widespread Loss of Heterozygosity and Endoreduplication in Odontogenic Myxoma: Expanding the Clinicopathologic Spectrum of An Enigmatic Odontogenic Neoplasm.

Odontogenic myxoma (OM) is an uncommon, locally aggressive odontogenic neoplasm with characteristic histologic and clinico-radiographic features but with potential for histologic overlap with other odontogenic and non-odontogenic entities and a non-specific immunoprofile. Widespread loss of heterozygosity (LOH) has been recently described in rare cases of OM. The aim of this study was to determine whether widespread LOH represents a recurrent molecular signature that can be leveraged for clinical decision-making. Allele-specific copy number variation data from chromosomal microarray were generated from 7 OM, comprising a combined prospective and retrospective cohort. Four tumors arose in the mandible and 3 in the maxilla in patients ranging in age from 18 to 94 years (median: 44), with tumor size ranging from 2.2 to 13.0 cm. Variable amounts of fibrous stroma (odontogenic "fibromyxoma") were present in 4/7 OM, and hypercellularity not typically appreciated in conventional OM was present in 3/7 cases. All OM (7/7) demonstrated widespread LOH, with 5 cases showing a near-haploid/low hypodiploid genomes (multiple monosomies) and 2 cases showing evidence of pseudo-hyperdiploidy due to probable endoreduplication. Both pseudo-hyperdiploid cases were ≥10 cm in size; 1 represented local recurrence. Chromosomes 1 to 3, 6, 9, 11, 13, 15, and 22 demonstrated LOH in ≥75% of cases (chromosomes 1 to 3, 6, and 9 in 100% of cases), while chromosomes 5, 12, 19, and 20 universally retained heterozygosity. Altogether, widespread LOH is a recurrent event in OM and a novel finding in odontogenic pathology, and allele-specific copy number variation analysis can serve as a diagnostic adjunct in challenging cases.

copy number variation↗
PubMed2003

Genomic instability and endoreduplication triggered by RAD17 deletion.

Cell cycle checkpoints are critical for genomic stability. Rad17, a component of the checkpoint clamp loader complex (Rad17/Rfc2-5), is required for the response to DNA damage and replication stress. To explore the role of Rad17 in the maintenance of genomic integrity, we established somatic conditional alleles of RAD17 in human cells. We find that RAD17 is not only important for the Atr-mediated checkpoint but is also essential for cell viability. Cells lacking RAD17 exhibited acute chromosomal aberrations and underwent endoreduplication at a high rate. Therefore, RAD17 links the checkpoint to ploidy control and is essential for the maintenance of chromosomal stability.

Blotting, Southern↗
PubMed2006

Hepatocytes with extensive telomere deprotection and fusion remain viable and regenerate liver mass through endoreduplication.

We report that mouse liver cells are highly resistant to extensive telomere dysfunction. In proliferating cells, telomere dysfunction results in chromosome end fusions, a DNA damage signal, and apoptosis or senescence. To determine the consequences of telomere dysfunction in noncycling cells, we used conditional deletion of the telomeric protein TRF2 in hepatocytes. TRF2 loss resulted in telomeric accumulation of gamma-H2AX and frequent telomere fusions, indicating telomere deprotection. However, there was no induction of p53 or apoptosis, and liver function appeared unaffected. Furthermore, the loss of TRF2 did not compromise liver regeneration after partial hepatectomy. Remarkably, liver regeneration occurred without cell division involving endoreduplication and cell growth, thereby circumventing the chromosome segregation problems associated with telomere fusions. We conclude that nondividing hepatocytes can maintain and regenerate liver function despite substantial loss of telomere integrity.

Animals↗