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Spindle checkpoint

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https://www.readbyqxmd.com/read/29165592/folate-deficiency-induces-mitotic-aberrations-and-chromosomal-instability-by-compromising-the-spindle-assembly-checkpoint-in-cultured-human-colon-cells
#1
Xihan Guo, Juan Ni, Yuqian Zhu, Tao Zhou, Xiaoling Ma, Jinglun Xue, Xu Wang
Folates comprise the essential B9 vitamin that act as cofactors and cosubstrates in one-carbon metabolism for both biosynthesis and methylation of DNA and RNA. Folate deficiency (FD) has been shown to induce chromosomal instability (CIN), yet the underlying mechanisms are poorly understood. Here, we used human NCM460 colon mucosal cells as a model to investigate the effect of FD on spindle assembly checkpoint (SAC), a cell-cycle regulatory pathway preventing CIN during mitosis. Cells were maintained in medium containing 1...
November 19, 2017: Mutagenesis
https://www.readbyqxmd.com/read/29162720/direct-interactions-of-mitotic-arrest-deficient-1-mad1-domains-with-each-other-and-mad2-conformers-are-required-for-mitotic-checkpoint-signaling
#2
Wenbin Ji, Yibo Luo, Ejaz Ahmad, Song-Tao Liu
As a sensitive signaling system, the mitotic checkpoint ensures faithful chromosome segregation by delaying anaphase onset even when a single kinetochore is unattached to mitotic spindle microtubules. The key signal amplification reaction for the checkpoint is the conformational conversion of "open" mitotic arrest deficient 2 (O-MAD2) into "closed" MAD2 (C-MAD2). The reaction has been suggested to be catalyzed by an unusual catalyst, a MAD1:C-MAD2 tetramer, but how the catalysis is executed and regulated remains elusive...
November 21, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29161843/mathematical-analysis-and-modeling-of-dna-segregation-mechanisms
#3
Bashar Ibrahim
The precise regulation of cell life division is indispensable to the reliable inheritance of genetic material, i.e. DNA, in successive generations of cells. This is governed by dedicated biochemical networks which ensure that all requirements are met before transition from one phase to the next. The Spindle Assembly Checkpoint (SAC) is an evolutionarily mechanism that delays mitotic progression until all chromosomes are properly linked to the mitotic spindle. During some asymmetric cell divisions, such as those observed in budding yeast, an additional mechanism, the Spindle Position Checkpoint (SPOC), is required to delay exit from mitosis until the mitotic spindle is correctly aligned...
April 1, 2018: Mathematical Biosciences and Engineering: MBE
https://www.readbyqxmd.com/read/29158164/lmo7-exerts-an-effect-on-mitosis-progression-and-the-spindle-assembly-checkpoint
#4
Yao-Wei Tzeng, Dai-Yu Li, Yvan Chen, Cheng-Hsiu Yang, Chih-Yun Chang, Yue-Li Juang
LMO7 (LIM domain only 7) is a transcription regulator for expression of many Emery-Dreifuss muscular dystrophy-relevant genes, and binds to α-actinin and AF6/afadin at adherens junctions for epithelial cell-cell adhesion. In this study, we found that human LMO7 interacted with the spindle assembly checkpoint (SAC) protein MAD1. LMO7 colocalized with actin filaments at the cell membrane but did not colocalize with MAD1 at kinetochores in prometaphase. Our observations reveal that overexpression but not depletion of LMO7 caused a SAC defect, and that the LIM domain of LMO7 was a determinant of its ability to interfere with kinetochore localization of the SAC proteins MAD2 and BUBR1 and cause a SAC defect though the LIM peptide itself did neither bind to MAD1, MAD2 and BUBR1 nor localize to the actin filaments...
November 17, 2017: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/29147457/oxidative-stress-delays-prometaphase-metaphase-of-the-first-cleavage-in-mouse-zygotes-via-the-mad2l1-mediated-spindle-assembly-checkpoint
#5
Que Wu, Zhiling Li, Yue Huang, Diting Qian, Man Chen, Wanfen Xiao, Bin Wang
In zygotes, DNA damage delays the first cleavage to enable repair. Our previous study found that 0.03 mM hydrogen peroxide (H2O2) was the minimum concentration required for induction of oxidative DNA damage in mouse zygotes and that this represented the most similar situation to the clinical phenomenon. In this study, we quantified the cleavage rates of cells in blastocysts at different developmental stages, followed by immunofluorescence to detect activation of γ-H2A histone family member X (a marker of DNA damage) in zygotes to confirm that oxidative DNA damage was induced in H2O2-treated zygotes...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/29129638/an-attachment-independent-biochemical-timer-of-the-spindle-assembly-checkpoint
#6
Junbin Qian, Maria Adelaida García-Gimeno, Monique Beullens, Maria Giulia Manzione, Gerd Van der Hoeven, Juan Carlos Igual, Miguel Heredia, Pascual Sanz, Lendert Gelens, Mathieu Bollen
The spindle assembly checkpoint (SAC) generates a diffusible protein complex that prevents anaphase until all chromosomes are properly attached to spindle microtubules. A key step in SAC initiation is the recruitment of MAD1 to kinetochores, which is generally thought to be governed by the microtubule-kinetochore (MT-KT) attachment status. However, we demonstrate that the recruitment of MAD1 via BUB1, a conserved kinetochore receptor, is not affected by MT-KT interactions in human cells. Instead, BUB1:MAD1 interaction depends on BUB1 phosphorylation, which is controlled by a biochemical timer that integrates counteracting kinase and phosphatase effects on BUB1 into a pulse-generating incoherent feedforward loop...
November 16, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29125603/cell-cycle-arrest-through-indirect-transcriptional-repression-by-p53-i-have-a-dream
#7
REVIEW
Kurt Engeland
Activation of the p53 tumor suppressor can lead to cell cycle arrest. The key mechanism of p53-mediated arrest is transcriptional downregulation of many cell cycle genes. In recent years it has become evident that p53-dependent repression is controlled by the p53-p21-DREAM-E2F/CHR pathway (p53-DREAM pathway). DREAM is a transcriptional repressor that binds to E2F or CHR promoter sites. Gene regulation and deregulation by DREAM shares many mechanistic characteristics with the retinoblastoma pRB tumor suppressor that acts through E2F elements...
November 10, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29123917/the-telomere-bouquet-facilitates-meiotic-prophase-progression-and-exit-in-fission-yeast
#8
Vera Moiseeva, Hanna Amelina, Laura C Collopy, Christine A Armstrong, Siân R Pearson, Kazunori Tomita
During meiotic prophase, chromosome arrangement and oscillation promote the pairing of homologous chromosomes for meiotic recombination. This dramatic movement involves clustering of telomeres at the nuclear membrane to form the so-called telomere bouquet. In fission yeast, the telomere bouquet is formed near the spindle pole body (SPB), which is the microtubule organising centre, functionally equivalent to the metazoan centrosome. Disruption of bouquet configuration impedes homologous chromosome pairing, meiotic recombination and spindle formation...
2017: Cell Discovery
https://www.readbyqxmd.com/read/29100415/the-e2f-activators-control-multiple-mitotic-regulators-and-maintain-genomic-integrity-through-sgo1-and-bubr1
#9
Miyoung Lee, Yainyrette Rivera-Rivera, Carlos S Moreno, Harold I Saavedra
The E2F1, E2F2, and E2F3a transcriptional activators control proliferation. However, how the E2F activators regulate mitosis to maintain genomic integrity is unclear. Centrosome amplification (CA) and unregulated spindle assembly checkpoint (SAC) are major generators of aneuploidy and chromosome instability (CIN) in cancer. Previously, we showed that overexpression of single E2F activators induced CA and CIN in mammary epithelial cells, and here we show that combined overexpression of E2F activators did not enhance CA...
September 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29100315/low-bub1-expression-is-an-adverse-prognostic-marker-in-gastric-adenocarcinoma
#10
David Stahl, Martin Braun, Andrew J Gentles, Philipp Lingohr, Adeline Walter, Glen Kristiansen, Ines Gütgemann
Gastric adenocarcinomas are associated with a poor prognosis due to the fact that the tumor has often metastasized by the time of diagnosis and prognostic markers are urgently needed to tailor treatment. We examined the expression of the mitotic spindle checkpoint protein BUB1 (budding uninhibited by benzimidazoles 1) and Ki-67 protein expression by immunohistochemistry in 218 patients with primary gastric adenocarcinomas. Tumors with low frequency of BUB1 expression were associated with larger tumor size (pT) (p < 0...
September 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29089159/the-importance-of-kinase-phosphatase-integration-lessons-from-mitosis
#11
REVIEW
Lendert Gelens, Junbin Qian, Mathieu Bollen, Adrian T Saurin
Kinases and phosphatases work antagonistically to control the behaviour of individual substrate molecules. This can be incorrectly extrapolated to imply that they also work antagonistically on the signals or processes that these molecules control. In fact, in many situations kinases and phosphatases work together to positively drive signal responses. We explain how this 'cooperativity' is critical for setting the amplitude, localisation, timing, and shape of phosphorylation signals. We use mitosis to illustrate why these properties are important for controlling mitotic entry, sister chromatid cohesion, kinetochore-microtubule attachments, the spindle assembly checkpoint, mitotic spindle elongation, and mitotic exit...
October 28, 2017: Trends in Cell Biology
https://www.readbyqxmd.com/read/29078282/rad52-phosphorylation-by-ipl1-and-mps1-contributes-to-mps1-kinetochore-localization-and-spindle-assembly-checkpoint-regulation
#12
Gyubum Lim, Won-Ki Huh
Rad52 is well known as a key factor in homologous recombination. Here, we report that Rad52 has functions unrelated to homologous recombination in Saccharomyces cerevisiae; it plays a role in the recruitment of Mps1 to the kinetochores and the maintenance of spindle assembly checkpoint (SAC) activity. Deletion of RAD52 causes various phenotypes related to the dysregulation of chromosome biorientation. Rad52 directly affects efficient operation of the SAC and accurate chromosome segregation. Remarkably, by using an in vitro kinase assay, we found that Rad52 is a substrate of Ipl1/Aurora and Mps1 in yeast and humans...
October 31, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29067790/sirt2-bubr1-acetylation-pathway-mediates-the-effects-of-advanced-maternal-age-on-oocyte-quality
#13
Danhong Qiu, Xiaojing Hou, Longsen Han, Xiaoyan Li, Juan Ge, Qiang Wang
The level of Sirt2 protein is reduced in oocytes from aged mice, while exogenous expression of Sirt2 could ameliorate the maternal age-associated meiotic defects. To date, the underlying mechanism remains unclear. Here, we confirmed that specific depletion of Sirt2 disrupts maturational progression and spindle/chromosome organization in mouse oocytes, with compromised kinetochore-microtubule attachments. Candidate screening revealed that acetylation state of lysine 243 on BubR1 (BubR1-K243, an integral part of the spindle assembly checkpoint complex) functions during oocyte meiosis, and acetylation-mimetic mutant BubR1-K243Q results in the very similar phenotypes as Sirt2-knockdown oocytes...
October 25, 2017: Aging Cell
https://www.readbyqxmd.com/read/29065308/the-spindle-assembly-checkpoint-in-arabidopsis-is-rapidly-shut-off-during-severe-stress
#14
Shinichiro Komaki, Arp Schnittger
The spindle assembly checkpoint (SAC) in animals and yeast assures equal segregation of chromosomes during cell division. The prevalent occurrence of polyploidy in flowering plants together with the observation that many plants can be readily forced to double their genomes by application of microtubule drugs raises the question of whether plants have a proper SAC. Here, we provide a functional framework of the core SAC proteins in Arabidopsis. We reveal that Arabidopsis will delay mitosis in a SAC-dependent manner if the spindle is perturbed...
October 23, 2017: Developmental Cell
https://www.readbyqxmd.com/read/29056333/the-spindle-assembly-checkpoint-is-required-for-hematopoietic-progenitor-cell-engraftment
#15
Andreas Brown, Johannes Pospiech, Karina Eiwen, Darren J Baker, Bettina Moehrle, Vadim Sakk, Kalpana Nattamai, Mona Vogel, Ani Grigoryan, Hartmut Geiger
The spindle assembly checkpoint plays a pivotal role in preventing aneuploidy and transformation. Many studies demonstrate impairment of this checkpoint in cancer cells. While leukemia is frequently driven by transformed hematopoietic stem and progenitor cells (HSPCs), the biology of the spindle assembly checkpoint in such primary cells is not very well understood. Here, we reveal that the checkpoint is fully functional in murine progenitor cells and, to a lesser extent, in hematopoietic stem cells. We show that HSPCs arrest at prometaphase and induce p53-dependent apoptosis upon prolonged treatment with anti-mitotic drugs...
November 14, 2017: Stem Cell Reports
https://www.readbyqxmd.com/read/29052525/epigenetic-mediated-zinc-finger-protein-671-downregulation-promotes-cell-proliferation-and-tumorigenicity-in-nasopharyngeal-carcinoma-by-inhibiting-cell-cycle-arrest
#16
Jian Zhang, Xin Wen, Na Liu, Ying-Qin Li, Xin-Ran Tang, Ya-Qin Wang, Qing-Mei He, Xiao-Jing Yang, Pan-Pan Zhang, Jun Ma, Ying Sun
BACKGROUND: Epigenetic abnormalities play important roles in nasopharyngeal cancer (NPC), however, the epigenetic changes associated with abnormal cell proliferation remain unclear. METHODS: We detected epigenetic change of ZNF671 in NPC tissues and cell lines by bisulfite pyrosequencing. We evaluated zinc finger protein 671 (ZNF671) expression in NPC cell lines and clinical tissues using real-time PCR and western blotting. Then, we established NPC cell lines that stably overexpressed ZNF671 and knocked down ZNF671 expression to explore its function in NPC in vitro and in vivo...
October 19, 2017: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/29046436/caenorhabditis-elegans-bub-3-and-san-1-mad3-spindle-assembly-checkpoint-components-are-required-for-genome-stability-in-response-to-treatment-with-ionizing-radiation
#17
Simone Bertolini, Bin Wang, Bettina Meier, Ye Hong, Anton Gartner
Relatively little is known about the crosstalk between the spindle assembly checkpoint and the DNA damage response, especially in multicellular organisms. We performed a Caenorhabditis elegans forward genetic screen to uncover new genes involved in the repair of DNA damage induced by ionizing radiation. We isolated a mutation, gt2000 which confers hypersensitivity to ionizing radiation and showed that gt2000 introduces a premature stop in bub-3 BUB-3 is a key component of the spindle assembly checkpoint. We provide evidence that BUB-3 acts during development and in the germline; irradiated bub-3(gt2000) larvae are developmentally retarded and form abnormal vulvae...
October 18, 2017: G3: Genes—Genomes—Genetics
https://www.readbyqxmd.com/read/29046339/a-checkpoint-independent-mechanism-delays-entry-into-mitosis-after-uv-irradiation
#18
Christiane Rothe, Gro Elise Rødland, Silje Anda, Vilte Stonyte, Erik Boye, Sandra Lopez-Aviles, Beáta Grallert
When cells are exposed to stress they delay entry into mitosis. The most extensively studied mechanism behind this delay is the DNA-damage-induced G2/M checkpoint. Here, we show the existence of an additional stress-response pathway which is independent of the classic ATR/Rad3-dependent checkpoint. This novel mechanism delays entry mitosis independent of the spindle assembly checkpoint and the mitotic kinases Fin1, Ark1 and Plo1. The pathway delays activation of the mitotic CDK, Cdc2, after UV irradiation. Furthermore, we demonstrate that translation of the mitotic cyclin Cdc13 is selectively downregulated after UV-irradiation and we propose that this downregulation of Cdc13 contributes to the delayed activation of Cdc2 and the delayed mitosis...
October 18, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/29040814/inhibiting-polo-like-kinase-1-plk1-enhances-radiosensitization-via-modulating-dna-repair-proteins-in-non-small-cell-lung-cancer
#19
Da Yao, Peigui Gu, Youyu Wang, Weibin Luo, Huiliang Chi, Jianjun Ge, Youhui Qian
To assure the faithful chromosome segregation, cells make use of the spindle assembly checkpoint (SAC), which can be activated in aneuploidy cancer cells. In this study, the efficacies of inhibiting Polo-like kinase 1 (PLK1) on the radiosensitization of non-small cell lung cancer (NSCLC) cells were studied. Clonogenic survival assay was performed to identify the effects of the PLK1 inhibitor on radiosensitivity within NSCLC cells. Mitotic catastrophe assessment was used to measure the cell death and γH2AX foci were utilized to assess the DNA double-strand breaks (DSB)...
October 17, 2017: Biochemistry and Cell Biology, Biochimie et Biologie Cellulaire
https://www.readbyqxmd.com/read/29040706/inhibition-of-survivin-expression-after-using-oxaliplatin-and-vinflunine-to-induce-cytogenetic-damage-in-vitro-in-lymphocytes-from-colon-cancer-patients-and-healthy-individuals
#20
Amal A A Alotaibi, Mojgan Najafzadeh, Justin D Davies, Adolf Baumgartner, Diana Anderson
Chemotherapy drugs usually inflict a lethal dose to tumour cells with the consequence that these cells are being killed by cell death. However, each round of chemotherapy also causes damage to normal somatic cells. The DNA cross-linking agent oxaliplatin (OXP), which causes DNA double-strand breaks, and vinflunine (VFN), which disrupts the mitotic spindle, are two of these chemotherapy drugs which were evaluated in vitro using peripheral lymphocytes from colorectal cancer patients and healthy individuals to determine any differential response...
October 17, 2017: Mutagenesis
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