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1
Ford, Judith Helen, and Anthony Thomas Correll. "Chromosome errors at mitotic anaphase." Genome 35, no. 4 (August 1, 1992): 702–5. http://dx.doi.org/10.1139/g92-107.
Повний текст джерелаАнотація:
Errors in mitotic divisions were assayed using various satellite DNAs as probes, hybridized in situ, to show that they included nondisjunction, chromosome and chromatid lagging, chromatid malsegregation, and monopolar segregations. The total rates of error were 1.7, 1.1, and 0.6% for chromosomes X, 17, and 18, respectively. Lagging was the most common error for all chromosomes and chromatid malsegregation, a source of 3:1 segregations occurred at about the same frequency as nondisjunction. In some cells, lagging of both X chromatids occurred and there were several cells where both X chromosomes showed errors in segregation. The disjunction of chromosomes was shown to be independent of their segregation and is speculated to involve a different mechanism.Key words: nondisjunction, lagging, in situ, satellite DNA, aneuploidy.
2
Sensi, Alberto, and Nicola Ricci. "Mitotic errors in trisomy 21." Nature Genetics 5, no. 3 (November 1993): 215. http://dx.doi.org/10.1038/ng1193-215a.
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3
Ha, Geun-Hyoung, and Eun-Kyoung Yim Breuer. "Mitotic Kinases and p53 Signaling." Biochemistry Research International 2012 (2012): 1–14. http://dx.doi.org/10.1155/2012/195903.
Повний текст джерелаАнотація:
Mitosis is tightly regulated and any errors in this process often lead to aneuploidy, genomic instability, and tumorigenesis. Deregulation of mitotic kinases is significantly associated with improper cell division and aneuploidy. Because of their importance during mitosis and the relevance to cancer, mitotic kinase signaling has been extensively studied over the past few decades and, as a result, several mitotic kinase inhibitors have been developed. Despite promising preclinical results, targeting mitotic kinases for cancer therapy faces numerous challenges, including safety and patient selection issues. Therefore, there is an urgent need to better understand the molecular mechanisms underlying mitotic kinase signaling and its interactive network. Increasing evidence suggests that tumor suppressor p53 functions at the center of the mitotic kinase signaling network. In response to mitotic spindle damage, multiple mitotic kinases phosphorylate p53 to either activate or deactivate p53-mediated signaling. p53 can also regulate the expression and function of mitotic kinases, suggesting the existence of a network of mutual regulation, which can be positive or negative, between mitotic kinases and p53 signaling. Therefore, deciphering this regulatory network will provide knowledge to overcome current limitations of targeting mitotic kinases and further improve the results of targeted therapy.
4
Elsing, Alexandra N., Camilla Aspelin, Johanna K. Björk, Heidi A. Bergman, Samu V. Himanen, Marko J. Kallio, Pia Roos-Mattjus, and Lea Sistonen. "Expression of HSF2 decreases in mitosis to enable stress-inducible transcription and cell survival." Journal of Cell Biology 206, no. 6 (September 8, 2014): 735–49. http://dx.doi.org/10.1083/jcb.201402002.
Повний текст джерелаАнотація:
Unless mitigated, external and physiological stresses are detrimental for cells, especially in mitosis, resulting in chromosomal missegregation, aneuploidy, or apoptosis. Heat shock proteins (Hsps) maintain protein homeostasis and promote cell survival. Hsps are transcriptionally regulated by heat shock factors (HSFs). Of these, HSF1 is the master regulator and HSF2 modulates Hsp expression by interacting with HSF1. Due to global inhibition of transcription in mitosis, including HSF1-mediated expression of Hsps, mitotic cells are highly vulnerable to stress. Here, we show that cells can counteract transcriptional silencing and protect themselves against proteotoxicity in mitosis. We found that the condensed chromatin of HSF2-deficient cells is accessible for HSF1 and RNA polymerase II, allowing stress-inducible Hsp expression. Consequently, HSF2-deficient cells exposed to acute stress display diminished mitotic errors and have a survival advantage. We also show that HSF2 expression declines during mitosis in several but not all human cell lines, which corresponds to the Hsp70 induction and protection against stress-induced mitotic abnormalities and apoptosis.
5
Green, Rebecca A., Roy Wollman, and Kenneth B. Kaplan. "APC and EB1 Function Together in Mitosis to Regulate Spindle Dynamics and Chromosome Alignment." Molecular Biology of the Cell 16, no. 10 (October 2005): 4609–22. http://dx.doi.org/10.1091/mbc.e05-03-0259.
Повний текст джерелаАнотація:
Recently, we have shown that a cancer causing truncation in adenomatous polyposis coli (APC) (APC1–1450) dominantly interferes with mitotic spindle function, suggesting APC regulates microtubule dynamics during mitosis. Here, we examine the possibility that APC mutants interfere with the function of EB1, a plus-end microtubule-binding protein that interacts with APC and is required for normal microtubule dynamics. We show that siRNA-mediated inhibition of APC, EB1, or APC and EB1 together give rise to similar defects in mitotic spindles and chromosome alignment without arresting cells in mitosis; in contrast inhibition of CLIP170 or LIS1 cause distinct spindle defects and mitotic arrest. We show that APC1–1450 acts as a dominant negative by forming a hetero-oligomer with the full-length APC and preventing it from interacting with EB1, which is consistent with a functional relationship between APC and EB1. Live-imaging of mitotic cells expressing EB1-GFP demonstrates that APC1–1450 compromises the dynamics of EB1-comets, increasing the frequency of EB1-GFP pausing. Together these data provide novel insight into how APC may regulate mitotic spindle function and how errors in chromosome segregation are tolerated in tumor cells.
6
Colicino, Erica G., Alice M. Garrastegui, Judy Freshour, Peu Santra, Dawn E. Post, Leszek Kotula, and Heidi Hehnly. "Gravin regulates centrosome function through PLK1." Molecular Biology of the Cell 29, no. 5 (March 2018): 532–41. http://dx.doi.org/10.1091/mbc.e17-08-0524.
Повний текст джерелаАнотація:
We propose to understand how the mitotic kinase PLK1 drives chromosome segregation errors, with a specific focus on Gravin, a PLK1 scaffold. In both three-dimensional primary prostate cancer cell cultures that are prone to Gravin depletion and Gravin short hairpin RNA (shRNA)–treated cells, an increase in cells containing micronuclei was noted in comparison with controls. To examine whether the loss of Gravin affected PLK1 distribution and activity, we utilized photokinetics and a PLK1 activity biosensor. Gravin depletion resulted in an increased PLK1 mobile fraction, causing the redistribution of active PLK1, which leads to increased defocusing and phosphorylation of the mitotic centrosome protein CEP215 at serine-613. Gravin depletion further led to defects in microtubule renucleation from mitotic centrosomes, decreased kinetochore-fiber integrity, increased incidence of chromosome misalignment, and subsequent formation of micronuclei following mitosis completion. Murine Gravin rescued chromosome misalignment and micronuclei formation, but a mutant Gravin that cannot bind PLK1 did not. These findings suggest that disruption of a Gravin–PLK1 interface leads to inappropriate PLK1 activity contributing to chromosome segregation errors, formation of micronuclei, and subsequent DNA damage.
7
Hut, Henderika M. J., Harm H. Kampinga, and Ody C. M. Sibon. "Hsp70 Protects Mitotic Cells against Heat-induced Centrosome Damage and Division Abnormalities." Molecular Biology of the Cell 16, no. 8 (August 2005): 3776–85. http://dx.doi.org/10.1091/mbc.e05-01-0038.
Повний текст джерелаАнотація:
The effect of heat shock on centrosomes has been mainly studied in interphase cells. Centrosomes play a key role in proper segregation of DNA during mitosis. However, the direct effect and consequences of heat shock on mitotic cells and a possible cellular defense system against proteotoxic stress during mitosis have not been described in detail. Here, we show that mild heat shock, applied during mitosis, causes loss of dynamitin/p50 antibody staining from centrosomes and kinetochores. In addition, it induces division errors in most cells and in the remaining cells progression through mitosis is delayed. Expression of heat shock protein (Hsp)70 protects against most heat-induced division abnormalities. On heat shock, Hsp70 is rapidly recruited to mitotic centrosomes and normal progression through mitosis is observed immediately after release of Hsp70 from centrosomes. In addition, Hsp70 expression coincides with restoration of dynamitin/p50 antibody staining at centrosomes but not at kinetochores. Our data show that during mitosis, centrosomes are particularly affected resulting in abnormal mitosis. Hsp70 is sufficient to protect against most division abnormalities, demonstrating the involvement of Hsp70 in a repair mechanism of heat-damaged mitotic centrosomes.
8
Carvalhal, Sara, Alexandra Tavares, Mariana B. Santos, Mihailo Mirkovic, and Raquel A. Oliveira. "A quantitative analysis of cohesin decay in mitotic fidelity." Journal of Cell Biology 217, no. 10 (July 12, 2018): 3343–53. http://dx.doi.org/10.1083/jcb.201801111.
Повний текст джерелаАнотація:
Sister chromatid cohesion mediated by cohesin is essential for mitotic fidelity. It counteracts spindle forces to prevent premature chromatid individualization and random genome segregation. However, it is unclear what effects a partial decline of cohesin may have on chromosome organization. In this study, we provide a quantitative analysis of cohesin decay by inducing acute removal of defined amounts of cohesin from metaphase-arrested chromosomes. We demonstrate that sister chromatid cohesion is very resistant to cohesin loss as chromatid disjunction is only observed when chromosomes lose >80% of bound cohesin. Removal close to this threshold leads to chromosomes that are still cohered but display compromised chromosome alignment and unstable spindle attachments. Partial cohesin decay leads to increased duration of mitosis and susceptibility to errors in chromosome segregation. We propose that high cohesin density ensures centromeric chromatin rigidity necessary to maintain a force balance with the mitotic spindle. Partial cohesin loss may lead to chromosome segregation errors even when sister chromatid cohesion is fulfilled.
9
Meyer, John S., Eric Cosatto, and Hans Peter Graf. "Mitotic Index of Invasive Breast Carcinoma." Archives of Pathology & Laboratory Medicine 133, no. 11 (November 1, 2009): 1826–33. http://dx.doi.org/10.5858/133.11.1826.
Повний текст джерелаАнотація:
Abstract Context.—Mitotic figure counts are related to breast cancer behavior but have not been sufficiently reproducible to be accepted for clinical decision-making. Objective.—To improve reproducibility and accuracy of the mitotic count. Design.—Mitotic index (MI) was defined as the mitotic cell count per 10 high-power fields (HPFs), an area 0.183 mm2. Two to 6 replicate sets of 10 HPFs were counted from 328 invasive breast carcinomas. Standard errors and coefficients of variation for mean MI were compared with expected results predicted by the binomial distribution. Results.—The boundaries for MI that separated the data into equal thirds (tertials) were 1.14 and 5.33. Standard errors and coefficients of variation for MI followed distributions predicted by binomial probability. Mean coefficient of variation was 147% for the low tertial, 72% for the midtertial, and 34.6% for the upper tertial. Conclusions.—Standard errors for MI based on a single count of 10 HPFs are too broad and coefficients of variation too large to be acceptable for clinical use. This is explained as a binomial probability effect, possibly with a contribution from tumor heterogeneity. Errors can be reduced in proportion to the square root of the number of sets of 10 HPFs counted. Tertial cutoffs of MI of the Nottingham system currently used in breast carcinoma grading are too high to be applicable to the population we studied. We recommend validation of cutoffs before they are applied to a particular population of breast carcinomas. Counting 5 sets of 10 HPFs is necessary to accurately rank carcinomas with low MIs.
10
Krem, Maxwell M., and Marshall S. Horwitz. "Mitotic errors, aneuploidy and micronuclei in Hodgkin lymphoma pathogenesis." Communicative & Integrative Biology 6, no. 3 (May 13, 2013): e23544. http://dx.doi.org/10.4161/cib.23544.
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11
Liu, Shiwei, Mijung Kwon, Mark Mannino, Nachen Yang, Fioranna Renda, Alexey Khodjakov, and David Pellman. "Nuclear envelope assembly defects link mitotic errors to chromothripsis." Nature 561, no. 7724 (September 2018): 551–55. http://dx.doi.org/10.1038/s41586-018-0534-z.
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12
Dewey, Evan B., and Christopher A. Johnston. "Diverse mitotic functions of the cytoskeletal cross-linking protein Shortstop suggest a role in Dynein/Dynactin activity." Molecular Biology of the Cell 28, no. 19 (September 15, 2017): 2555–68. http://dx.doi.org/10.1091/mbc.e17-04-0219.
Повний текст джерелаАнотація:
Proper assembly and orientation of the bipolar mitotic spindle is critical to the fidelity of cell division. Mitotic precision fundamentally contributes to cell fate specification, tissue development and homeostasis, and chromosome distribution within daughter cells. Defects in these events are thought to contribute to several human diseases. The underlying mechanisms that function in spindle morphogenesis and positioning remain incompletely defined, however. Here we describe diverse roles for the actin-microtubule cross-linker Shortstop (Shot) in mitotic spindle function in Drosophila. Shot localizes to mitotic spindle poles, and its knockdown results in an unfocused spindle pole morphology and a disruption of proper spindle orientation. Loss of Shot also leads to chromosome congression defects, cell cycle progression delay, and defective chromosome segregation during anaphase. These mitotic errors trigger apoptosis in Drosophila epithelial tissue, and blocking this apoptotic response results in a marked induction of the epithelial–mesenchymal transition marker MMP-1. The actin-binding domain of Shot directly interacts with Actin-related protein-1 (Arp-1), a key component of the Dynein/Dynactin complex. Knockdown of Arp-1 phenocopies Shot loss universally, whereas chemical disruption of F-actin does so selectively. Our work highlights novel roles for Shot in mitosis and suggests a mechanism involving Dynein/Dynactin activation.
13
Ricke, Robin M., Karthik B. Jeganathan, Liviu Malureanu, Andrew M. Harrison, and Jan M. van Deursen. "Bub1 kinase activity drives error correction and mitotic checkpoint control but not tumor suppression." Journal of Cell Biology 199, no. 6 (December 3, 2012): 931–49. http://dx.doi.org/10.1083/jcb.201205115.
Повний текст джерелаАнотація:
The mitotic checkpoint protein Bub1 is essential for embryogenesis and survival of proliferating cells, and bidirectional deviations from its normal level of expression cause chromosome missegregation, aneuploidy, and cancer predisposition in mice. To provide insight into the physiological significance of this critical mitotic regulator at a modular level, we generated Bub1 mutant mice that lack kinase activity using a knockin gene-targeting approach that preserves normal protein abundance. In this paper, we uncover that Bub1 kinase activity integrates attachment error correction and mitotic checkpoint signaling by controlling the localization and activity of Aurora B kinase through phosphorylation of histone H2A at threonine 121. Strikingly, despite substantial chromosome segregation errors and aneuploidization, mice deficient for Bub1 kinase activity do not exhibit increased susceptibility to spontaneous or carcinogen-induced tumorigenesis. These findings provide a unique example of a modular mitotic activity orchestrating two distinct networks that safeguard against whole chromosome instability and reveal the differential importance of distinct aneuploidy-causing Bub1 defects in tumor suppression.
14
Serpico, Angela Flavia, and Domenico Grieco. "Recent advances in understanding the role of Cdk1 in the Spindle Assembly Checkpoint." F1000Research 9 (January 28, 2020): 57. http://dx.doi.org/10.12688/f1000research.21185.1.
Повний текст джерелаАнотація:
The goal of mitosis is to form two daughter cells each containing one copy of each mother cell chromosome, replicated in the previous S phase. To achieve this, sister chromatids held together back-to-back at their primary constriction, the centromere, have to interact with microtubules of the mitotic spindle so that each chromatid takes connections with microtubules emanating from opposite spindle poles (we will refer to this condition as bipolar attachment). Only once all replicated chromosomes have reached bipolar attachments can sister chromatids lose cohesion with each other, at the onset of anaphase, and move toward opposite spindle poles, being segregated into what will soon become the daughter cell nucleus. Prevention of errors in chromosome segregation is granted by a safeguard mechanism called Spindle Assembly Checkpoint (SAC). Until all chromosomes are bipolarly oriented at the equator of the mitotic spindle, the SAC prevents loss of sister chromatid cohesion, thus anaphase onset, and maintains the mitotic state by inhibiting inactivation of the major M phase promoting kinase, the cyclin B-cdk1 complex (Cdk1). Here, we review recent mechanistic insights about the circuitry that links Cdk1 to the SAC to ensure correct achievement of the goal of mitosis.
15
Fraschini, Roberta, Denis Bilotta, Giovanna Lucchini, and Simonetta Piatti. "Functional Characterization of Dma1 and Dma2, the Budding Yeast Homologues of Schizosaccharomyces pombe Dma1 and Human Chfr." Molecular Biology of the Cell 15, no. 8 (August 2004): 3796–810. http://dx.doi.org/10.1091/mbc.e04-02-0094.
Повний текст джерелаАнотація:
Proper transmission of genetic information requires correct assembly and positioning of the mitotic spindle, responsible for driving each set of sister chromatids to the two daughter cells, followed by cytokinesis. In case of altered spindle orientation, the spindle position checkpoint inhibits Tem1-dependent activation of the mitotic exit network (MEN), thus delaying mitotic exit and cytokinesis until errors are corrected. We report a functional analysis of two previously uncharacterized budding yeast proteins, Dma1 and Dma2, 58% identical to each other and homologous to human Chfr and Schizosaccharomyces pombe Dma1, both of which have been previously implicated in mitotic checkpoints. We show that Dma1 and Dma2 are involved in proper spindle positioning, likely regulating septin ring deposition at the bud neck. DMA2 overexpression causes defects in septin ring disassembly at the end of mitosis and in cytokinesis. The latter defects can be rescued by either eliminating the spindle position checkpoint protein Bub2 or overproducing its target, Tem1, both leading to MEN hyperactivation. In addition, dma1Δ dma2Δ cells fail to activate the spindle position checkpoint in response to the lack of dynein, whereas ectopic expression of DMA2 prevents unscheduled mitotic exit of spindle checkpoint mutants treated with microtubule-depolymerizing drugs. Although their primary functions remain to be defined, our data suggest that Dma1 and Dma2 might be required to ensure timely MEN activation in telophase.
16
Silkworth, William T., and Daniela Cimini. "Transient defects of mitotic spindle geometry and chromosome segregation errors." Cell Division 7, no. 1 (2012): 19. http://dx.doi.org/10.1186/1747-1028-7-19.
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Lanza, Chris, Ee Phie Tan, Zhen Zhang, Miranda Machacek, Amanda E. Brinker, Mizuki Azuma, and Chad Slawson. "Reduced O-GlcNAcase expression promotes mitotic errors and spindle defects." Cell Cycle 15, no. 10 (April 12, 2016): 1363–75. http://dx.doi.org/10.1080/15384101.2016.1167297.
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18
Levine, Michelle S., and Andrew J. Holland. "The impact of mitotic errors on cell proliferation and tumorigenesis." Genes & Development 32, no. 9-10 (May 1, 2018): 620–38. http://dx.doi.org/10.1101/gad.314351.118.
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19
Tavormina, P. A., Y. Wang, and D. J. Burke. "Differential requirements for DNA replication in the activation of mitotic checkpoints in Saccharomyces cerevisiae." Molecular and Cellular Biology 17, no. 6 (June 1997): 3315–22. http://dx.doi.org/10.1128/mcb.17.6.3315.
Повний текст джерелаАнотація:
Checkpoints prevent inaccurate chromosome segregation by inhibiting cell division when errors in mitotic processes are encountered. We used a temperature-sensitive mutation, dbf4, to examine the requirement for DNA replication in establishing mitotic checkpoint arrest. We used gamma-irradiation to induce DNA damage and hydroxyurea to limit deoxyribonucleotides in cells deprived of DBF4 function to investigate the requirement for DNA replication in DNA-responsive checkpoints. In the absence of DNA replication, mitosis was not inhibited by these treatments, which normally activate the DNA damage and DNA replication checkpoints. Our results support a model that indicates that the assembly of replication structures is critical for cells to respond to defects in DNA metabolism. We show that activating the spindle checkpoint with nocodazole does not require prior progression through S phase but does require a stable kinetochore.
20
Pedley, Robert, and Andrew P. Gilmore. "Mitosis and mitochondrial priming for apoptosis." Biological Chemistry 397, no. 7 (July 1, 2016): 595–605. http://dx.doi.org/10.1515/hsz-2016-0134.
Повний текст джерелаАнотація:
Abstract Cell division is a period of danger for cells, as inaccurate segregation of chromosomes can lead to loss of cell viability or aneuploidy. In order to protect against these dangers, cells ultimately initiate mitochondrial apoptosis if they are unable to correctly exit mitosis. A number of important chemotherapeutics exploit this response to delayed mitotic exit, but despite this, the molecular mechanism of the apoptotic timer in mitosis has proved elusive. Some recent studies have now shed light on this, showing how passage through the cell cycle fine-tunes a cell’s apoptotic sensitivity such that it can respond appropriately when errors arise.
21
Stormo, Benjamin M., and Donald T. Fox. "Interphase cohesin regulation ensures mitotic fidelity after genome reduplication." Molecular Biology of the Cell 30, no. 2 (January 15, 2019): 219–27. http://dx.doi.org/10.1091/mbc.e17-10-0582.
Повний текст джерелаАнотація:
To ensure faithful genome propagation, mitotic cells alternate one round of chromosome duplication with one round of chromosome separation. Chromosome separation failure thus causes genome reduplication, which alters mitotic chromosome structure. Such structural alterations are well documented to impair mitotic fidelity following aberrant genome reduplication, including in diseased states. In contrast, we recently showed that naturally occurring genome reduplication does not alter mitotic chromosome structure in Drosophila papillar cells. Our discovery raised the question of how a cell undergoing genome reduplication might regulate chromosome structure to prevent mitotic errors. Here, we show that papillar cells ensure mitotic fidelity through interphase cohesin regulation. We demonstrate a requirement for cohesins during programmed rounds of papillar genome reduplication known as endocycles. This interphase cohesin regulation relies on cohesin release but not cohesin cleavage and depends on the conserved cohesin regulator Pds5 . Our data suggest that a distinct form of interphase cohesin regulation ensures mitotic fidelity after genome reduplication.
22
Nguyen, Christine L., and Karl Münger. "Human Papillomavirus E7 Protein Deregulates Mitosis via an Association with Nuclear Mitotic Apparatus Protein 1." Journal of Virology 83, no. 4 (December 3, 2008): 1700–1707. http://dx.doi.org/10.1128/jvi.01971-08.
Повний текст джерелаАнотація:
ABSTRACT We previously observed that high-risk human papillomavirus type 16 (HPV16) E7 expression leads to the delocalization of dynein from mitotic spindles (C. L. Nguyen, M. E. McLaughlin-Drubin, and K. Munger, Cancer Res. 68:8715-8722, 2008). Here, we show that HPV16 E7 associates with nuclear mitotic apparatus protein 1 (NuMA) and that NuMA binding and the ability to induce dynein delocalization map to similar carboxyl-terminal sequences of E7. Additionally, we show that the delocalization of dynein from mitotic spindles by HPV16 E7 and the interaction between HPV16 E7 and NuMA correlate with the induction of defects in chromosome alignment during prometaphase even in cells with normal centrosome numbers. Furthermore, low-risk HPV6b and HPV11 E7s also associate with NuMA and also induce a similar mitotic defect. It is possible that the disruption of mitotic events by HPV E7, via targeting of the NuMA/dynein complex and potentially other NuMA-containing complexes, contributes to viral maintenance and propagation potentially through abrogating the differentiation program of the infected epithelium. Furthermore, in concert with activities specific to high-risk HPV E6 and E7, such as the inactivation of the p53 and pRB tumor suppressors, respectively, the disruption of the NuMA/dynein network may result in mitotic errors that would make an infected cell more prone to the accumulation of aneuploidy even in the absence of supernumerary centrosomes.
23
Fujibayashi, Yuto, Reiko Isa, Daichi Nishiyama, Natsumi Sakamoto-Inada, Norichika Kawasumi, Junko Yamaguchi, Saeko Kuwahara-Ota, et al. "Aberrant BUB1 Overexpression Promotes Mitotic Segregation Errors and Chromosomal Instability in Multiple Myeloma." Cancers 12, no. 8 (August 6, 2020): 2206. http://dx.doi.org/10.3390/cancers12082206.
Повний текст джерелаАнотація:
Chromosome instability (CIN), the hallmarks of cancer, reflects ongoing chromosomal changes caused by chromosome segregation errors and results in whole chromosomal or segmental aneuploidy. In multiple myeloma (MM), CIN contributes to the acquisition of tumor heterogeneity, and thereby, to disease progression, drug resistance, and eventual treatment failure; however, the underlying mechanism of CIN in MM remains unclear. Faithful chromosomal segregation is tightly regulated by a series of mitotic checkpoint proteins, such as budding uninhibited by benzimidazoles 1 (BUB1). In this study, we found that BUB1 was overexpressed in patient-derived myeloma cells, and BUB1 expression was significantly higher in patients in an advanced stage compared to those in an early stage. This suggested the involvement of aberrant BUB1 overexpression in disease progression. In human myeloma-derived cell lines (HMCLs), BUB1 knockdown reduced the frequency of chromosome segregation errors in mitotic cells. In line with this, partial knockdown of BUB1 showed reduced variations in chromosome number compared to parent cells in HMCLs. Finally, BUB1 overexpression was found to promote the clonogenic potency of HMCLs. Collectively, these results suggested that enhanced BUB1 expression caused an increase in mitotic segregation errors and the resultant emergence of subclones with altered chromosome numbers and, thus, was involved in CIN in MM.
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Antao, Ainsley Mike, Kamini Kaushal, Soumyadip Das, Vijai Singh, Bharathi Suresh, Kye-Seong Kim, and Suresh Ramakrishna. "USP48 Governs Cell Cycle Progression by Regulating the Protein Level of Aurora B." International Journal of Molecular Sciences 22, no. 16 (August 7, 2021): 8508. http://dx.doi.org/10.3390/ijms22168508.
Повний текст джерелаАнотація:
Deubiquitinating enzymes play key roles in the precise modulation of Aurora B—an essential cell cycle regulator. The expression of Aurora B increases before the onset of mitosis and decreases during mitotic exit; an imbalance in these levels has a severe impact on the fate of the cell cycle. Dysregulation of Aurora B can lead to aberrant chromosomal segregation and accumulation of errors during mitosis, eventually resulting in cytokinesis failure. Thus, it is essential to identify the precise regulatory mechanisms that modulate Aurora B levels during the cell division cycle. Using a deubiquitinase knockout strategy, we identified USP48 as an important candidate that can regulate Aurora B protein levels during the normal cell cycle. Here, we report that USP48 interacts with and stabilizes the Aurora B protein. Furthermore, we showed that the deubiquitinating activity of USP48 helps to maintain the steady-state levels of Aurora B protein by regulating its half-life. Finally, USP48 knockout resulted in delayed progression of cell cycle due to accumulation of mitotic defects and ultimately cytokinesis failure, suggesting the role of USP48 in cell cycle regulation.
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Vicente, Juan-Jesus, and W. Zacheus Cande. "Mad2, Bub3, and Mps1 regulate chromosome segregation and mitotic synchrony in Giardia intestinalis, a binucleate protist lacking an anaphase-promoting complex." Molecular Biology of the Cell 25, no. 18 (September 15, 2014): 2774–87. http://dx.doi.org/10.1091/mbc.e14-05-0975.
Повний текст джерелаАнотація:
The binucleate pathogen Giardia intestinalis is a highly divergent eukaryote with a semiopen mitosis, lacking an anaphase-promoting complex/cyclosome (APC/C) and many of the mitotic checkpoint complex (MCC) proteins. However, Giardia has some MCC components (Bub3, Mad2, and Mps1) and proteins from the cohesin system (Smc1 and Smc3). Mad2 localizes to the cytoplasm, but Bub3 and Mps1 are either located on chromosomes or in the cytoplasm, depending on the cell cycle stage. Depletion of Bub3, Mad2, or Mps1 resulted in a lowered mitotic index, errors in chromosome segregation (including lagging chromosomes), and abnormalities in spindle morphology. During interphase, MCC knockdown cells have an abnormal number of nuclei, either one nucleus usually on the left-hand side of the cell or two nuclei with one mislocalized. These results suggest that the minimal set of MCC proteins in Giardia play a major role in regulating many aspects of mitosis, including chromosome segregation, coordination of mitosis between the two nuclei, and subsequent nuclear positioning. The critical importance of MCC proteins in an organism that lacks their canonical target, the APC/C, suggests a broader role for these proteins and hints at new pathways to be discovered.
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Carloni, Vinicio, Matteo Lulli, Stefania Madiai, Tommaso Mello, Andrew Hall, Tu Vinh Luong, Massimo Pinzani, Krista Rombouts, and Andrea Galli. "CHK2 overexpression and mislocalisation within mitotic structures enhances chromosomal instability and hepatocellular carcinoma progression." Gut 67, no. 2 (March 30, 2017): 348–61. http://dx.doi.org/10.1136/gutjnl-2016-313114.
Повний текст джерелаАнотація:
ObjectiveChromosomal instability (CIN) is the most common form of genomic instability, which promotes hepatocellular carcinoma (HCC) progression by enhancing tumour heterogeneity, drug resistance and immunity escape. CIN per se is an important factor of DNA damage, sustaining structural chromosome abnormalities but the underlying mechanisms are unknown.DesignDNA damage response protein checkpoint kinase 2 (Chk2) expression was evaluated in an animal model of diethylnitrosamine-induced HCC characterised by DNA damage and elevated mitotic errors. Chk2 was also determined in two discrete cohorts of human HCC specimens. To assess the functional role of Chk2, gain on and loss-of-function, mutagenesis, karyotyping and immunofluorescence/live imaging were performed by using HCT116, Huh7 and human hepatocytes immortalised with hTERT gene (HuS).ResultsWe demonstrate that mitotic errors during HCC tumorigenesis cause lagging chromosomes/DNA damage and activation of Chk2. Overexpression/phosphorylation and mislocalisation within the mitotic spindle of Chk2 contributes to induce lagging chromosomes. Lagging chromosomes and mitotic activity are reversed by knockdown of Chk2. Furthermore, upregulated Chk2 maintains mitotic activity interacting with Aurora B kinase for chromosome condensation and cytokinesis. The forkhead-associated domain of Chk2 is required for Chk2 mislocalisation to mitotic structures. In addition, retinoblastoma protein phosphorylation contributes to defective mitoses. A cohort and independent validation cohort show a strong cytoplasm to nuclear Chk2 translocation in a subset of patients with HCC.ConclusionsThe study reveals a new mechanistic insight in the coinvolvement of Chk2 in HCC progression. These findings propose Chk2 as a putative biomarker to detect CIN in HCC providing a valuable support for clinical/therapeutical management of patients.
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Loeper, S., B. F. M. Romeike, N. Heckmann, V. Jung, W. Henn, W. Feiden, K. D. Zang, and S. Urbschat. "Frequent mitotic errors in tumor cells of genetically micro-heterogeneous glioblastomas." Cytogenetic and Genome Research 94, no. 1-2 (2001): 1–8. http://dx.doi.org/10.1159/000048773.
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Jin, Yuesheng, Ylva Stewénius, David Lindgren, Attila Frigyesi, Olga Calcagnile, Tord Jonson, Anna Edqvist, et al. "Distinct Mitotic Segregation Errors Mediate Chromosomal Instability in Aggressive Urothelial Cancers." Clinical Cancer Research 13, no. 6 (March 15, 2007): 1703–12. http://dx.doi.org/10.1158/1078-0432.ccr-06-2705.
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Carvalhal, Sara, Susana Abreu Ribeiro, Miguel Arocena, Taciana Kasciukovic, Achim Temme, Katrin Koehler, Angela Huebner, and Eric R. Griffis. "The nucleoporin ALADIN regulates Aurora A localization to ensure robust mitotic spindle formation." Molecular Biology of the Cell 26, no. 19 (October 2015): 3424–38. http://dx.doi.org/10.1091/mbc.e15-02-0113.
Повний текст джерелаАнотація:
The formation of the mitotic spindle is a complex process that requires massive cellular reorganization. Regulation by mitotic kinases controls this entire process. One of these mitotic controllers is Aurora A kinase, which is itself highly regulated. In this study, we show that the nuclear pore protein ALADIN is a novel spatial regulator of Aurora A. Without ALADIN, Aurora A spreads from centrosomes onto spindle microtubules, which affects the distribution of a subset of microtubule regulators and slows spindle assembly and chromosome alignment. ALADIN interacts with inactive Aurora A and is recruited to the spindle pole after Aurora A inhibition. Of interest, mutations in ALADIN cause triple A syndrome. We find that some of the mitotic phenotypes that we observe after ALADIN depletion also occur in cells from triple A syndrome patients, which raises the possibility that mitotic errors may underlie part of the etiology of this syndrome.
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Wilhelm, Therese, Maha Said, and Valeria Naim. "DNA Replication Stress and Chromosomal Instability: Dangerous Liaisons." Genes 11, no. 6 (June 10, 2020): 642. http://dx.doi.org/10.3390/genes11060642.
Повний текст джерелаАнотація:
Chromosomal instability (CIN) is associated with many human diseases, including neurodevelopmental or neurodegenerative conditions, age-related disorders and cancer, and is a key driver for disease initiation and progression. A major source of structural chromosome instability (s-CIN) leading to structural chromosome aberrations is “replication stress”, a condition in which stalled or slowly progressing replication forks interfere with timely and error-free completion of the S phase. On the other hand, mitotic errors that result in chromosome mis-segregation are the cause of numerical chromosome instability (n-CIN) and aneuploidy. In this review, we will discuss recent evidence showing that these two forms of chromosomal instability can be mechanistically interlinked. We first summarize how replication stress causes structural and numerical CIN, focusing on mechanisms such as mitotic rescue of replication stress (MRRS) and centriole disengagement, which prevent or contribute to specific types of structural chromosome aberrations and segregation errors. We describe the main outcomes of segregation errors and how micronucleation and aneuploidy can be the key stimuli promoting inflammation, senescence, or chromothripsis. At the end, we discuss how CIN can reduce cellular fitness and may behave as an anticancer barrier in noncancerous cells or precancerous lesions, whereas it fuels genomic instability in the context of cancer, and how our current knowledge may be exploited for developing cancer therapies.
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Poulton, John S., John C. Cuningham, and Mark Peifer. "Centrosome and spindle assembly checkpoint loss leads to neural apoptosis and reduced brain size." Journal of Cell Biology 216, no. 5 (March 28, 2017): 1255–65. http://dx.doi.org/10.1083/jcb.201607022.
Повний текст джерелаАнотація:
Accurate mitotic spindle assembly is critical for mitotic fidelity and organismal development. Multiple processes coordinate spindle assembly and chromosome segregation. Two key components are centrosomes and the spindle assembly checkpoint (SAC), and mutations affecting either can cause human microcephaly. In vivo studies in Drosophila melanogaster found that loss of either component alone is well tolerated in the developing brain, in contrast to epithelial tissues of the imaginal discs. In this study, we reveal that one reason for that tolerance is the compensatory relationship between centrosomes and the SAC. In the absence of both centrosomes and the SAC, brain cells, including neural stem cells, experience massive errors in mitosis, leading to increased cell death, which reduces the neural progenitor pool and severely disrupts brain development. However, our data also demonstrate that neural cells are much more tolerant of aneuploidy than epithelial cells. Our data provide novel insights into the mechanisms by which different tissues manage genome stability and parallels with human microcephaly.
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Bergman, Lee M., Charles N. Birts, Matthew Darley, Brian Gabrielli, and Jeremy P. Blaydes. "CtBPs Promote Cell Survival through the Maintenance of Mitotic Fidelity." Molecular and Cellular Biology 29, no. 16 (June 8, 2009): 4539–51. http://dx.doi.org/10.1128/mcb.00439-09.
Повний текст джерелаАнотація:
ABSTRACT CtBPs (CtBP1 and CtBP2) act in the nucleus as transcriptional corepressors and in the cytoplasm as regulators of Golgi apparatus fission. Studies in which the expression or function of CtBPs has been inhibited have independently identified roles for CtBPs in both suppressing apoptosis and promoting cell cycle progression. Here, we have analyzed the consequences of ablating CtBP expression in breast cancer-derived cell lines. We found that loss of CtBP expression suppresses cell proliferation through a combination of apoptosis, reduction in cell cycle progression, and aberrations in transit through mitosis. The third phenotype includes errors in mitotic chromosome segregation that are associated with decreased association of the chromosome passenger protein aurora B with mitotic chromatin and that are likely to be a primary cause of the proapoptotic and antiproliferative effects of CtBP loss. We also show that loss of CtBP expression results in the activation of the transcription factor p53 and that loss of p53 function renders cells more susceptible to CtBP small interfering RNA-induced apoptosis.
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Galardy, Paul J., and Ying Zhang. "USP44 Is Highly Over-Expresed In T-Cell Acute Lymphoblastic Leukemia and Leads to the Development of Chromosome Missegregation and Aneupoloidy." Blood 116, no. 21 (November 19, 2010): 29. http://dx.doi.org/10.1182/blood.v116.21.29.29.
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Abstract Abstract 29 Acute lymphoblastic leukemia (ALL) cells are frequently characterized by abnormal numbers of chromosomes, a condition known as aneuploidy. Aneuploidy in ALL is not just a curiosity, but impacts on the prognosis and risk stratification in children. Additionally, aneuploidy itself contributes to the development of cancer by dysregulating gene expression, and driving the loss of heterozygosity of mutated tumor suppressor genes. The molecular underpinnings of aneuploidy in ALL are largely unknown. The mitotic checkpoint is a complex pathway that acts in mitosis to prevent the premature onset of anaphase that leads to improper segregation of chromosomes and aneuploidy. Through the concerted action of many intermediates, the mitotic checkpoint functions to inhibit the activity of a large ubiquitin E3 ligase complex known as the anaphase promoting complex/cyclosome (APC/C) that drives the separation of paired sister chromatids by effecting the ubiquitin-dependent degradation of cyclin B1 and securin. The de-ubiquitinating enzyme USP44 was recently identified as an important regulator of mitotic progression that assists in maintaining mitotic checkpoint signaling until all chromosomes are properly attached to the mitotic spindle. Microarray studies of childhood acute leukemias have observed high levels of USP44 in T-cell ALL, but the significance of this observation is unclear. Here we show that USP44 is indeed over-expressed in T-ALL in children and that its presence may contribute to aneuploidy that is frequently observed in this disease. We compared the expression of USP44 in a series of 24 samples from patients with T-ALL to that found in ten samples of peripheral T-cells isolated from healthy donors, using quantitative real-time PCR. There was a dramatic increase in the expression of USP44 in T-ALL with 18 out of 24 cases having at least 3-fold increase, with an average of 16-fold increase, in USP44 mRNA. We next studied the consequences of USP44 over-expression in primary cells using live-cell microscopy. We find that excess USP44 leads to dramatic and significant increase in chromosome missegregation with most defects involving lagging chromosomes due to improper chromosome attachment to the mitotic spindle. We observe that these mitotic errors lead to the development of aneuploidy, through a mechanism that requires USP44 catalytic activity. These effects are accompanied by reinforced mitotic checkpoint signaling that leads to delayed progression through mitosis, and a prolonged duration of mitotic arrest in cells exposed to spindle poisons such as nocodazole or paclitaxel. At the molecular level, we observe that excess USP44 leads to enhanced binding of the mitotic checkpoint effector Mad2 to the APC/C and increased levels of cyclin B1 in early mitosis. Taken together, we conclude that USP44 is a chromosome instability gene that is frequently expressed at high levels in T-ALL cells, and that this may contribute to the pathogenesis of T-ALL by leading to chromosome shuffling and aneuploidy. These data have important implications in our understanding of the pathogenesis of this disease and may contribute to understanding the therapeutic effectiveness of novel aurora inhibitors in cancer. Disclosures: No relevant conflicts of interest to declare.
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Keating, Leonor, Sandra A. Touati, and Katja Wassmann. "A PP2A-B56—Centered View on Metaphase-to-Anaphase Transition in Mouse Oocyte Meiosis I." Cells 9, no. 2 (February 7, 2020): 390. http://dx.doi.org/10.3390/cells9020390.
Повний текст джерелаАнотація:
Meiosis is required to reduce to haploid the diploid genome content of a cell, generating gametes—oocytes and sperm—with the correct number of chromosomes. To achieve this goal, two specialized cell divisions without intermediate S-phase are executed in a time-controlled manner. In mammalian female meiosis, these divisions are error-prone. Human oocytes have an exceptionally high error rate that further increases with age, with significant consequences for human fertility. To understand why errors in chromosome segregation occur at such high rates in oocytes, it is essential to understand the molecular players at work controlling these divisions. In this review, we look at the interplay of kinase and phosphatase activities at the transition from metaphase-to-anaphase for correct segregation of chromosomes. We focus on the activity of PP2A-B56, a key phosphatase for anaphase onset in both mitosis and meiosis. We start by introducing multiple roles PP2A-B56 occupies for progression through mitosis, before laying out whether or not the same principles may apply to the first meiotic division in oocytes, and describing the known meiosis-specific roles of PP2A-B56 and discrepancies with mitotic cell cycle regulation.
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Stavropoulou, Vaia, Jianjun Xie, Marie Henriksson, Birgitta Tomkinson, Stefan Imreh, and Maria G. Masucci. "Mitotic Infidelity and Centrosome Duplication Errors in Cells Overexpressing Tripeptidyl-Peptidase II." Cancer Research 65, no. 4 (February 15, 2005): 1361–68. http://dx.doi.org/10.1158/0008-5472.can-04-2085.
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Hood, Emily A., Arminja N. Kettenbach, Scott A. Gerber, and Duane A. Compton. "Plk1 regulates the kinesin-13 protein Kif2b to promote faithful chromosome segregation." Molecular Biology of the Cell 23, no. 12 (June 15, 2012): 2264–74. http://dx.doi.org/10.1091/mbc.e11-12-1013.
Повний текст джерелаАнотація:
Solid tumors are frequently aneuploid, and many display high rates of ongoing chromosome missegregation in a phenomenon called chromosomal instability (CIN). The most common cause of CIN is the persistence of aberrant kinetochore-microtubule (k-MT) attachments, which manifest as lagging chromosomes in anaphase. k-MT attachment errors form during prometaphase due to stochastic interactions between kinetochores and microtubules. The kinesin-13 protein Kif2b promotes the correction of k-MT attachment errors in prometaphase, but the mechanism restricting this activity to prometaphase remains unknown. Using mass spectrometry, we identified multiple phosphorylation sites on Kif2b, some of which are acutely sensitive to inhibition of Polo-like kinase 1 (Plk1). We show that Plk1 directly phosphorylates Kif2b at threonine 125 (T125) and serine 204 (S204), and that these two sites differentially regulate Kif2b function. Phosphorylation of S204 is required for the kinetochore localization and activity of Kif2b in prometaphase, and phosphorylation of T125 is required for Kif2b activity in the correction of k-MT attachment errors. These data demonstrate that Plk1 regulates both the localization and activity of Kif2b during mitosis to promote the correction of k-MT attachment errors to ensure mitotic fidelity.
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Tan, Ee Phie, Sarah Caro, Anish Potnis, Christopher Lanza, and Chad Slawson. "O-Linked N-Acetylglucosamine Cycling Regulates Mitotic Spindle Organization." Journal of Biological Chemistry 288, no. 38 (August 14, 2013): 27085–99. http://dx.doi.org/10.1074/jbc.m113.470187.
Повний текст джерелаАнотація:
Any defects in the correct formation of the mitotic spindle will lead to chromosomal segregation errors, mitotic arrest, or aneuploidy. We demonstrate that O-linked N-acetylglucosamine (O-GlcNAc), a post-translational modification of serine and threonine residues in nuclear and cytoplasmic proteins, regulates spindle function. In O-GlcNAc transferase or O-GlcNAcase gain of function cells, the mitotic spindle is incorrectly assembled. Chromosome condensation and centrosome assembly is impaired in these cells. The disruption in spindle architecture is due to a reduction in histone H3 phosphorylation by Aurora kinase B. However, gain of function cells treated with the O-GlcNAcase inhibitor Thiamet-G restored the assembly of the spindle and partially rescued histone phosphorylation. Together, these data suggest that the coordinated addition and removal of O-GlcNAc, termed O-GlcNAc cycling, regulates mitotic spindle organization and provides a potential new perspective on how O-GlcNAc regulates cellular events.
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Su, Hsing-Hao, Hung-Wei Pan, Chuan-Pin Lu, Jyun-Jie Chuang, and Tsan Yang. "Automatic Detection Method for Cancer Cell Nucleus Image Based on Deep-Learning Analysis and Color Layer Signature Analysis Algorithm." Sensors 20, no. 16 (August 7, 2020): 4409. http://dx.doi.org/10.3390/s20164409.
Повний текст джерелаАнотація:
Exploring strategies to treat cancer has always been an aim of medical researchers. One of the available strategies is to use targeted therapy drugs to make the chromosomes in cancer cells unstable such that cell death can be induced, and the elimination of highly proliferative cancer cells can be achieved. Studies have reported that the mitotic defects and micronuclei in cancer cells can be used as biomarkers to evaluate the instability of the chromosomes. Researchers use these two biomarkers to assess the effects of drugs on eliminating cancer cells. However, manual work is required to count the number of cells exhibiting mitotic defects and micronuclei either directly from the viewing window of a microscope or from an image, which is tedious and creates errors. Therefore, this study aims to detect cells with mitotic defects and micronuclei by applying an approach that can automatically count the targets. This approach integrates the application of a convolutional neural network for normal cell identification and the proposed color layer signature analysis (CLSA) to spot cells with mitotic defects and micronuclei. This approach provides a method for researchers to detect colon cancer cells in an accurate and time-efficient manner, thereby decreasing errors and the processing time. The following sections will illustrate the methodology and workflow design of this study, as well as explain the practicality of the experimental comparisons and the results that were used to validate the practicality of this algorithm.
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Lopes, Danilo, and Helder Maiato. "The Tubulin Code in Mitosis and Cancer." Cells 9, no. 11 (October 26, 2020): 2356. http://dx.doi.org/10.3390/cells9112356.
Повний текст джерелаАнотація:
The “tubulin code” combines different α/β-tubulin isotypes with several post-translational modifications (PTMs) to generate microtubule diversity in cells. During cell division, specific microtubule populations in the mitotic spindle are differentially modified, but only recently, the functional significance of the tubulin code, with particular emphasis on the role specified by tubulin PTMs, started to be elucidated. This is the case of α-tubulin detyrosination, which was shown to guide chromosomes during congression to the metaphase plate and allow the discrimination of mitotic errors, whose correction is required to prevent chromosomal instability—a hallmark of human cancers implicated in tumor evolution and metastasis. Although alterations in the expression of certain tubulin isotypes and associated PTMs have been reported in human cancers, it remains unclear whether and how the tubulin code has any functional implications for cancer cell properties. Here, we review the role of the tubulin code in chromosome segregation during mitosis and how it impacts cancer cell properties. In this context, we discuss the existence of an emerging “cancer tubulin code” and the respective implications for diagnostic, prognostic and therapeutic purposes.
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Hardwick, Kevin G., Rong Li, Cathy Mistrot, Rey-Huei Chen, Phoebe Dann, Adam Rudner, and Andrew W. Murray. "Lesions in Many Different Spindle Components Activate the Spindle Checkpoint in the Budding Yeast Saccharomyces cerevisiae." Genetics 152, no. 2 (June 1, 1999): 509–18. http://dx.doi.org/10.1093/genetics/152.2.509.
Повний текст джерелаАнотація:
Abstract The spindle checkpoint arrests cells in mitosis in response to defects in the assembly of the mitotic spindle or errors in chromosome alignment. We determined which spindle defects the checkpoint can detect by examining the interaction of mutations that compromise the checkpoint (mad1, mad2, and mad3) with those that damage various structural components of the spindle. Defects in microtubule polymerization, spindle pole body duplication, microtubule motors, and kinetochore components all activate the MAD-dependent checkpoint. In contrast, the cell cycle arrest caused by mutations that induce DNA damage (cdc13), inactivate the cyclin proteolysis machinery (cdc16 and cdc23), or arrest cells in anaphase (cdc15) is independent of the spindle checkpoint.
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Nicklas, R. B., and S. C. Ward. "Elements of error correction in mitosis: microtubule capture, release, and tension." Journal of Cell Biology 126, no. 5 (September 1, 1994): 1241–53. http://dx.doi.org/10.1083/jcb.126.5.1241.
Повний текст джерелаАнотація:
The correction of certain errors in mitosis requires capture and release: new kinetochore microtubules must be captured and old, misdirected ones must be released. We studied capture and release in living grasshopper spermatocytes. Capture is remarkably efficient over a broad range in the angle at which a microtubule encounters a kinetochore. However, capture is inefficient when kinetochores point directly away from the source of properly directed microtubules. Capture in that situation is required for correction of the most common error; microtubule-kinetochore encounters are improbable and capture occurs only once every 8 min, on average. Release from the improper attachment caused by misdirected microtubules allows kinetochore movement and the completion of error correction. We tugged on kinetochores with a micromanipulation needle and found they are free to move less than one time in two. Thus error correction depends on two improbable events, capture and release, and they must happen by chance to coincide. In spermatocytes this will occur only once every 18 min, on average, but a leisurely cell cycle provides ample time. Capture and release generate only change, not perfection. Tension from mitotic forces brings change to a halt by stabilizing the one correct attachment of chromosomes to the spindle. We show that tension directly affects stability, rather than merely constraining kinetochore position. This implies that chromosomes are attached to the spindle by tension-sensitive linkers whose stability is necessary for proper chromosome distribution but whose loss is necessary for the correction of errors.
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Liu, Xu, Leilei Xu, Junying Li, Phil Y. Yao, Wanjuan Wang, Hazrat Ismail, Haowei Wang, et al. "Mitotic motor CENP-E cooperates with PRC1 in temporal control of central spindle assembly." Journal of Molecular Cell Biology 12, no. 8 (September 10, 2019): 654–65. http://dx.doi.org/10.1093/jmcb/mjz051.
Повний текст джерелаАнотація:
Abstract Error-free cell division depends on the accurate assembly of the spindle midzone from dynamic spindle microtubules to ensure chromatid segregation during metaphase–anaphase transition. However, the mechanism underlying the key transition from the mitotic spindle to central spindle before anaphase onset remains elusive. Given the prevalence of chromosome instability phenotype in gastric tumorigenesis, we developed a strategy to model context-dependent cell division using a combination of light sheet microscope and 3D gastric organoids. Light sheet microscopic image analyses of 3D organoids showed that CENP-E inhibited cells undergoing aberrant metaphase–anaphase transition and exhibiting chromosome segregation errors during mitosis. High-resolution real-time imaging analyses of 2D cell culture revealed that CENP-E inhibited cells undergoing central spindle splitting and chromosome instability phenotype. Using biotinylated syntelin as an affinity matrix, we found that CENP-E forms a complex with PRC1 in mitotic cells. Chemical inhibition of CENP-E in metaphase by syntelin prevented accurate central spindle assembly by perturbing temporal assembly of PRC1 to the midzone. Thus, CENP-E-mediated PRC1 assembly to the central spindle constitutes a temporal switch to organize dynamic kinetochore microtubules into stable midzone arrays. These findings reveal a previously uncharacterized role of CENP-E in temporal control of central spindle assembly. Since CENP-E is absent from yeast, we reasoned that metazoans evolved an elaborate central spindle organization machinery to ensure accurate sister chromatid segregation during anaphase and cytokinesis.
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Rattray, Alison J., Carolyn B. McGill, Brenda K. Shafer, and Jeffrey N. Strathern. "Fidelity of Mitotic Double-Strand-Break Repair in Saccharomyces cerevisiae: A Role for SAE2/COM1." Genetics 158, no. 1 (May 1, 2001): 109–22. http://dx.doi.org/10.1093/genetics/158.1.109.
Повний текст джерелаАнотація:
Abstract Errors associated with the repair of DNA double-strand breaks (DSBs) include point mutations caused by misincorporation during repair DNA synthesis or novel junctions made by nonhomologous end joining (NHEJ). We previously demonstrated that DNA synthesis is ∼100-fold more error prone when associated with DSB repair. Here we describe a genetic screen for mutants that affect the fidelity of DSB repair. The substrate consists of inverted repeats of the trp1 and CAN1 genes. Recombinational repair of a site-specific DSB within the repeat yields TRP1 recombinants. Errors in the repair process can be detected by the production of canavanine-resistant (can1) mutants among the TRP1 recombinants. In wild-type cells the recombinational repair process is efficient and fairly accurate. Errors resulting in can1 mutations occur in <1% of the TRP1 recombinants and most appear to be point mutations. We isolated several mutant strains with altered fidelity of recombination. Here we characterize one of these mutants that revealed an ∼10-fold elevation in the frequency of can1 mutants among TRP1 recombinants. The gene was cloned by complementation of a coincident sporulation defect and proved to be an allele of SAE2/COM1. Physical analysis of the can1 mutants from sae2/com1 strains revealed that many were a novel class of chromosome rearrangement that could reflect break-induced replication (BIR) and NHEJ. Strains with either the mre11s-H125N or rad50s-K81I alleles had phenotypes in this assay that are similar to that of the sae2/com1Δ strain. Our data suggest that Sae2p/Com1p plays a role in ensuring that both ends of a DSB participate in a recombination event, thus avoiding BIR, possibly by regulating the nuclease activity of the Mre11p/Rad50p/Xrs2p complex.
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Tasselli, Luisa, Yuanxin Xi, Wei Zheng, Ruth I. Tennen, Zaneta Odrowaz, Federica Simeoni, Wei Li, and Katrin F. Chua. "SIRT6 deacetylates H3K18ac at pericentric chromatin to prevent mitotic errors and cellular senescence." Nature Structural & Molecular Biology 23, no. 5 (April 4, 2016): 434–40. http://dx.doi.org/10.1038/nsmb.3202.
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Krem, Maxwell M., Ping Luo, Brandon I. Ing, and Marshall S. Horwitz. "The Kelch Protein KLHDC8B Guards against Mitotic Errors, Centrosomal Amplification, and Chromosomal Instability." Journal of Biological Chemistry 287, no. 46 (September 17, 2012): 39083–93. http://dx.doi.org/10.1074/jbc.m112.390088.
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Özer, Özgün, and Ian D. Hickson. "Pathways for maintenance of telomeres and common fragile sites during DNA replication stress." Open Biology 8, no. 4 (April 2018): 180018. http://dx.doi.org/10.1098/rsob.180018.
Повний текст джерелаАнотація:
Oncogene activation during tumour development leads to changes in the DNA replication programme that enhance DNA replication stress. Certain regions of the human genome, such as common fragile sites and telomeres, are particularly sensitive to DNA replication stress due to their inherently ‘difficult-to-replicate’ nature. Indeed, it appears that these regions sometimes fail to complete DNA replication within the period of interphase when cells are exposed to DNA replication stress. Under these conditions, cells use a salvage pathway, termed ‘mitotic DNA repair synthesis (MiDAS)’, to complete DNA synthesis in the early stages of mitosis. If MiDAS fails, the ensuing mitotic errors threaten genome integrity and cell viability. Recent studies have provided an insight into how MiDAS helps cells to counteract DNA replication stress. However, our understanding of the molecular mechanisms and regulation of MiDAS remain poorly defined. Here, we provide an overview of how DNA replication stress triggers MiDAS, with an emphasis on how common fragile sites and telomeres are maintained. Furthermore, we discuss how a better understanding of MiDAS might reveal novel strategies to target cancer cells that maintain viability in the face of chronic oncogene-induced DNA replication stress.
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Sarkar, Sourav, Ellis L. Ryan, and Stephen J. Royle. "FGFR3–TACC3 cancer gene fusions cause mitotic defects by removal of endogenous TACC3 from the mitotic spindle." Open Biology 7, no. 8 (August 2017): 170080. http://dx.doi.org/10.1098/rsob.170080.
Повний текст джерелаАнотація:
Fibroblast growth factor receptor 3–transforming acidic coiled-coil containing protein 3 (FGFR3–TACC3; FT3) is a gene fusion resulting from rearrangement of chromosome 4 that has been identified in many cancers including those of the urinary bladder. Altered FGFR3 signalling in FT3-positive cells is thought to contribute to cancer progression. However, potential changes in TACC3 function in these cells have not been explored. TACC3 is a mitotic spindle protein required for accurate chromosome segregation. Errors in segregation lead to aneuploidy, which can contribute to cancer progression. Here we show that FT3-positive bladder cancer cells have lower levels of endogenous TACC3 on the mitotic spindle, and that this is sufficient to cause mitotic defects. FT3 is not localized to the mitotic spindle, and by virtue of its TACC domain, recruits endogenous TACC3 away from the spindle. Knockdown of the fusion gene or low-level overexpression of TACC3 partially rescues the chromosome segregation defects in FT3-positive bladder cancer cells. This function of FT3 is specific to TACC3 as inhibition of FGFR3 signalling does not rescue the TACC3 level on the spindle in these cancer cells. Models of FT3-mediated carcinogenesis should, therefore, include altered mitotic functions of TACC3 as well as altered FGFR3 signalling.
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Schnerch, Dominik, Julia Felthaus, Lara Mentlein, Monika Engelhardt, and Ralph M. Waesch. "Analysis of Mitosis In Acute Myeloid Leukemia Using Live-Cell Imaging." Blood 116, no. 21 (November 19, 2010): 3363. http://dx.doi.org/10.1182/blood.v116.21.3363.3363.
Повний текст джерелаАнотація:
Abstract Abstract 3363 Proper mitotic control is a prerequisite to guarantee the equal distribution of the genetic material onto the two developing daughter cells. A mitotic key regulator is cyclin B. High levels of cyclin B facilitate entry into mitosis whereas its controlled degradation coordinates chromosome separation and cytokinesis. The latter events are coordinated by the anaphase- promoting complex / cyclosome (APC/C), a ubiquitin ligase that couples ubiquitin chains to cyclin B, mediating its proteasomal degradation. The regulation of the APC/C-activity by complex protein networks, such as the spindle assembly checkpoint, therefore presents the basis for an accurate mitosis. Mitotic errors give rise to daughter cells with an aberrant set of chromosomes and contribute to genetic instability. Genetic instability is a hallmark of cancer cells and plays an important role in the onset and progression of acute myeloid leukemia (AML). In rare cases, de novo AMLs present with multiple cytogenetic aberrations (complex karyotype). However, a larger number of patients develop karyotype deviations in the course of the disease, sometimes even under therapy, which comes along with an adverse prognosis. Understanding the biology that drives the gain and loss of genetic material therefore bears the potential of identifying new therapeutic targets. We compared a number of lymphoblastic and myeloid cell lines and found AML cell lines to be deficient in arresting at metaphase in the presence of the microtubule-disrupting agent nocodazole. Cyclin B was expressed at much lower levels in the AML cell line Kasumi-1 and did not accumulate following spindle disruption as observed in the lymphoblastic cell line DG-75. We could show that Kasumi-1 cells, when challenged with nocodazole, were not capable of properly maintaining chromatid-cohesion and underwent premature sister chromatid separation. These findings suggest that mitotic control mechanisms do not work tightly enough in AML cells to prevent chromosome separation in the presence of spindle disruption. We applied live-cell imaging to exactly characterize mitotic timing in Kasumi-1 cells at a single cell level. The expression of a GFP-tagged derivative of histone H2 served to visualize the nuclear envelope breakdown and anaphase onset. Detection of the latter events allowed the faithful measurement of mitotic timing. We could find a significant shortening of mitosis in Kasumi-1 cells as compared to the lymphoblastic cell line DG-75. In both AML cell lines and primary AML blasts we identified the spindle assembly checkpoint components BubR1 and Bub1 to be downregulated. Interestingly, re-expression of BubR1 in Kasumi-1 cells led to a significant stabilization of cyclin B on western blots. To address the question whether an increased expression of cyclin B leads to a more pronounced mitotic delay in the presence of spindle-disruption in AML cells is subject of current experiments. It was reported that different cell types can escape from a mitotic block as a consequence of cyclin B degradation. In the literature, this phenomenon was referred to as mitotic slippage and is known to drive genetic instability. To monitor cyclin B turnover and localization at a single cell level, we generated a chimeric cyclin B-molecule, SNAP-cyclin B, which can couple to a suitable fluorochrome in a self-labeling reaction after addition to the growth medium. In this system, the fluorescence intensity reflects the amount of chimeric cyclin B and allows the monitoring of APC/C-dependent proteolysis. In our current approaches we aim at studying cyclin B-turnover at a single cell level in AML cell lines as well as primary leukemia cells by using live-cell imaging before and after BubR1- and Bub1-rescue. An aberrant cell cycle control is found in most human malignancies and might be an important driving force in leukemogenesis. We hypothesize that BubR1, in concert with different other regulators, might lead to inaccuracies in mitotic control. This hypothesis is underlined by the shortened time to anaphase in Kasumi-1 cells and a decreased expression of cyclin B, both of which are characteristics of BubR1-depletion. Mitotic regulators are already targets in AML therapy and a deeper understanding of mitotic processes in AML might lead to improved approaches. Disclosures: No relevant conflicts of interest to declare.
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Kim, Taekyung. "Recent Progress on the Localization of PLK1 to the Kinetochore and Its Role in Mitosis." International Journal of Molecular Sciences 23, no. 9 (May 8, 2022): 5252. http://dx.doi.org/10.3390/ijms23095252.
Повний текст джерелаАнотація:
The accurate distribution of the replicated genome during cell division is essential for cell survival and healthy organismal development. Errors in this process have catastrophic consequences, such as birth defects and aneuploidy, a hallmark of cancer cells. PLK1 is one of the master kinases in mitosis and has multiple functions, including mitotic entry, chromosome segregation, spindle assembly checkpoint, and cytokinesis. To dissect the role of PLK1 in mitosis, it is important to understand how PLK1 localizes in the specific region in cells. PLK1 localizes at the kinetochore and is essential in spindle assembly checkpoint and chromosome segregation. However, how PLK1 localizes at the kinetochore remains elusive. Here, we review the recent literature on the kinetochore recruitment mechanisms of PLK1 and its roles in spindle assembly checkpoint and attachment between kinetochores and spindle microtubules. Together, this review provides an overview of how the local distribution of PLK1 could regulate major pathways in mitosis.
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Kai, Yoshiteru, Hiroomi Kawano, and Naoki Yamashita. "First mitotic spindle formation is led by sperm centrosome-dependent MTOCs in humans." Reproduction 161, no. 5 (May 2021): V19—V22. http://dx.doi.org/10.1530/rep-21-0061.
Повний текст джерелаАнотація:
Unlike in mice, multinucleated blastomeres appear at a high frequency in the two-cell-stage embryos in humans. In this Point of View article, we demonstrate that the first mitotic spindle formation led by sperm centrosome-dependent microtubule organizing centers may cause a high incidence of zygotic division errors using human tripronuclear zygotes.