The Consequences of Chromosome Segregation Errors in Mitosis and Meiosis

Potapova, Tamara; Gorbsky, Gary J.

doi:10.3390/biology6010012

Cited by 159 publications

(128 citation statements)

References 271 publications

(315 reference statements)

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“…These observations introduce the possibility that chromosome segregation errors associated with exposure to PDGF-AA may underlie the malignant transformation of stem-like cells in which p53 or its pathway has been compromised. Indeed, segregation errors can induce mitotic arrest (27), DNA breaks (28) and apoptosis (27) and lead to gains and losses of whole chromosomes (29), features that have been documented in our system. Intriguingly, the areas of recurrent losses in our model harbor GBM-associated tumour suppressor genes.…”

Section: Discussionsupporting

confidence: 54%

Beyond Conventional Models: Recreating the Initiation, Evolution, and Genome of GBM

Böhm

DePetro

Binding

et al. 2019

Preprint

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Background: Imagining ways to prevent or treat glioblastoma (GBM) have been hindered by a lack of understanding of its pathogenesis. Although PDGF-AA overexpression may be an early event, critical details of the core biology are lacking. Existing PDGF-driven models replicate its microscopic appearance but not the genomic architecture characteristic of the human disease.Here we report a new model of GBM that overcomes this barrier to authenticity. Methods:Using a method developed to study neural stem cells, we investigated the effects of PDGF-AA on subventricular zone (SVZ) cells, the putative cell of origin of GBM. We micro-dissected SVZ tissue from p53-null and wild-type adult mice, established primary cultures in media supplemented with PDGF-AA, and assessed cell viability, proliferation, genome stability, and tumour forming potential. Results: Counterintuitive to its canonical role as a growth factor, we observed immediate and massive death of SVZ cells in PDGF-AA. Wild-type cells did not survive in PDGF-AA. However, a small fraction of null cells evaded apoptosis, displayed attenuated proliferation, gradually accumulated whole chromosome gains and losses, and, signalled by sudden rapid proliferation and growth factor independence, became tumorigenic in immune-competent syngeneic mice. Transformed cells had an OPC-like profile, were resistant to PDGFR-α inhibition, and harboured highly abnormal karyotypes similar to those seen in human GBMs. Conclusion: This model associates genome instability in SVZ cells with chronic exposure to PDGF-AA; it is the first model to replicate the genomic landscape of GBM and first in which the earliest phases of GBM can be directly observed. IMPORTANCE OF STUDYWe have developed a mouse model in which the initiation, evolution and genomic landscape of GBM can be thoroughly studied thus paving the way for ideas about how this deadly brain cancer might be prevented, interrupted at an occult stage, or treated with very different therapies.

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Section: Discussionsupporting

confidence: 54%

Beyond Conventional Models: Recreating the Initiation, Evolution, and Genome of GBM

Böhm

DePetro

Binding

et al. 2019

Preprint

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“…To better understand the behaviour and characteristics of the chromosomes that give rise to laggards at anaphase, we analysed 10 MII oocytes that contained 15 laggards at anaphase (Fig and Movie EV3). The lagging chromatids did not delay anaphase II onset (Fig EV5A) and did not give rise to micronuclei, the latter in contrast to what have been observed in mitotic cells . Centromere tracking revealed that the 15 lagging chromatids observed at anaphase II originated from 13 laggard‐producing chromosomes.…”

Section: Resultsmentioning

confidence: 76%

Post‐metaphase correction of aberrant kinetochore‐microtubule attachments in mammalian eggs

et al. 2019

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The accuracy of the two sequential meiotic divisions in oocytes is essential for creating a haploid gamete with a normal chromosomal content. Here, we have analysed the 3D dynamics of chromosomes during the second meiotic division in live mouse oocytes. We find that chromosomes form stable kinetochore–microtubule attachments at the end of prometaphase II stage that are retained until anaphase II onset. Remarkably, we observe that more than 20% of the kinetochore–microtubule attachments at the metaphase II stage are merotelic or lateral. However, < 1% of all chromosomes at onset of anaphase II are found to lag at the spindle equator and < 10% of the laggards missegregate and give rise to aneuploid gametes. Our results demonstrate that aberrant kinetochore–microtubule attachments are not corrected at the metaphase stage of the second meiotic division. Thus, the accuracy of the chromosome segregation process in mouse oocytes during meiosis II is ensured by an efficient correction process acting at the anaphase stage.

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“…Aneuploidy derived from mitotic slippage caused genomic instability, since it showed an abnormal number of chromosomes [76,78,79], and subsequent cell death or senescence in a process known as mitotic catastrophe [65,74,80]. In addition, cell death induced by electric fields was caspase dependent, but the first triggers of the caspase-dependent apoptosis were not known [65].…”

Section: Discussionmentioning

confidence: 99%

Cell Death and Induced p53 Expression in Oral Cancer, HeLa, and Bone Marrow Mesenchyme Cells under the Exposure to Noncontact Electric Fields

Mujib¹,

Alamsyah²,

Taruno³

2017

Integr Med Int

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Background: p53 acts as a transcription factor to regulate the expression of genes that modulate various cellular activities. The proliferation of cancer cells has been inhibited under the exposure to low-intensity (18 peak-to-peak voltage) and intermediate-frequency (100 KHz) electric fields generated between 2 capacitive electrodes. Therefore, the aims of this study were to observe the molecular mechanism of cell death caused by noncontact electric field exposure and to determine whether p53 protein can serve as a biomarker for this exposure or not. Methods: Oral squamous cell carcinoma, HeLa, and bone marrow mesenchyme cells were exposed to noncontact electric fields of Electro-Capacitive Cancer Therapy (ECCT) for 24 h. To observe the mechanism of cell death caused by ECCT, immunocytochemistry of p53 was performed, and the p53 expression was evaluated using immunoreactive score (IRS) calculation. Results: Electric field exposure by ECCT increased the percentage of dead cells in oral cancer cells (18.39%), HeLa cells (6.60%), and bone marrow mesenchyme cells (34.05%) with statistical significance using the independent t test compared to each control group. The IRS of p53 in oral cancer, HeLa, and bone marrow mesenchyme cultures were 10.50, 11.25, and 4.94, respectively. Conclusion: The high IRS shown in the treated oral cancer and HeLa culture cells may suggest that p53 expression in these culture cells is associated with the cell death mechanism induced by the exposure to noncontact electric fields, and the increased cell death in these culture cells may correlate with the IRS.

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The Consequences of Chromosome Segregation Errors in Mitosis and Meiosis

Cited by 159 publications

References 271 publications

Beyond Conventional Models: Recreating the Initiation, Evolution, and Genome of GBM

Beyond Conventional Models: Recreating the Initiation, Evolution, and Genome of GBM

Post‐metaphase correction of aberrant kinetochore‐microtubule attachments in mammalian eggs

Cell Death and Induced p53 Expression in Oral Cancer, HeLa, and Bone Marrow Mesenchyme Cells under the Exposure to Noncontact Electric Fields

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