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Spindle Assembly Checkpoint

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https://www.readbyqxmd.com/read/29129638/an-attachment-independent-biochemical-timer-of-the-spindle-assembly-checkpoint
#1
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 8, 2017: Molecular Cell
https://www.readbyqxmd.com/read/29125603/cell-cycle-arrest-through-indirect-transcriptional-repression-by-p53-i-have-a-dream
#2
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/29100415/the-e2f-activators-control-multiple-mitotic-regulators-and-maintain-genomic-integrity-through-sgo1-and-bubr1
#3
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/29089159/the-importance-of-kinase-phosphatase-integration-lessons-from-mitosis
#4
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
#5
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
#6
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
#7
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
#8
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/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
#9
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
#10
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
#11
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/29021254/checkpoint-kinase-1-induced-phosphorylation-of-o-linked-%C3%AE-n-acetylglucosamine-transferase-regulates-the-intermediate-filament-network-during-cytokinesis
#12
Zhe Li, Xueyan Li, Shanshan Nai, Qizhi Geng, Ji Liao, Xingzhi Xu, Jing Li
Checkpoint kinase 1 (Chk1) is a kinase instrumental for orchestrating DNA replication, DNA damage checkpoints, the spindle assembly checkpoint and cytokinesis. Despite Chk1's pivotal role in multiple cellular processes, many of its substrates remain elusive. Here, we identified O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) as one of Chk1's substrates. We found that Chk1 interacts with and phosphorylates OGT at Ser-20, which not only stabilizes OGT, but also is required for cytokinesis. Phospho-specific antibodies of OGT-pSer-20 exhibited specific signals at the midbody of the cell, consistent with midbody localization of OGT as previously reported...
October 11, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29021232/pkc%C3%AE%C2%B5-controls-mitotic-progression-by-regulating-centrosome-migration-and-mitotic-spindle-assembly
#13
Silvia Martini, Tanya Soliman, Giuliana Gobbi, Prisco Mirandola, Cecilia Carubbi, Elena Masselli, Giulia Pozzi, Peter J Parker, Marco Vitale
To form a proper mitotic spindle, centrosomes must be duplicated and driven poleward in a timely and controlled fashion. Improper timing of centrosome separation and errors in mitotic spindle assembly may lead to chromosome instability, a hallmark of cancer. Protein Kinase C epsilon (PKCε) has recently emerged as a regulator of several cell cycle processes associated with the resolution of mitotic catenation during the metaphase-anaphase transition and in regulating the abscission checkpoint. However, an engagement of PKCε in earlier (pre)mitotic events has not been addressed...
October 11, 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29017056/mitotic-spindle-assembly-and-genomic-stability-in-breast-cancer-require-pi3k-c2%C3%AE-scaffolding-function
#14
Federico Gulluni, Miriam Martini, Maria Chiara De Santis, Carlo Cosimo Campa, Alessandra Ghigo, Jean Piero Margaria, Elisa Ciraolo, Irene Franco, Ugo Ala, Laura Annaratone, Davide Disalvatore, Giovanni Bertalot, Giuseppe Viale, Anna Noatynska, Mara Compagno, Sara Sigismund, Filippo Montemurro, Marcus Thelen, Fan Fan, Patrick Meraldi, Caterina Marchiò, Salvatore Pece, Anna Sapino, Roberto Chiarle, Pier Paolo Di Fiore, Emilio Hirsch
Proper organization of the mitotic spindle is key to genetic stability, but molecular components of inter-microtubule bridges that crosslink kinetochore fibers (K-fibers) are still largely unknown. Here we identify a kinase-independent function of class II phosphoinositide 3-OH kinase α (PI3K-C2α) acting as limiting scaffold protein organizing clathrin and TACC3 complex crosslinking K-fibers. Downregulation of PI3K-C2α causes spindle alterations, delayed anaphase onset, and aneuploidy, indicating that PI3K-C2α expression is required for genomic stability...
October 9, 2017: Cancer Cell
https://www.readbyqxmd.com/read/28985013/hdac2-3-binding-and-deacetylation-of-bubr1-initiates-the-spindle-assembly-checkpoint-silencing
#15
Inai Park, Mi-Sun Kwon, Sangjin Paik, Hyeonjong Kim, Hae-Ock Lee, Eunhee Choi, Hyunsook Lee
BubR1 acetylation is essential in spindle assembly checkpoint (SAC) signaling. Here we show that BubR1 deacetylation is a signal that initiates the mitotic exit. Sustained BubR1 acetylation arrests the cells in metaphase, although chromosome congression is achieved. BubR1 deacetylation was coordinated with dephosphorylation in mitotic exit, suggesting the presence of a coordinated acetylation-phosphorylation code in mitotic signaling. HDAC2 and 3 bound to acetylated BubR1 exclusively in mitosis and led to the polyubiquitination of BubR1...
October 6, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28978643/chromosome-biorientation-and-apc-activity-remain-uncoupled-in-oocytes-with-reduced-volume
#16
Simon I R Lane, Keith T Jones
The spindle assembly checkpoint (SAC) prevents chromosome missegregation by coupling anaphase onset with correct chromosome attachment and tension to microtubules. It does this by generating a diffusible signal from free kinetochores into the cytoplasm, inhibiting the anaphase-promoting complex (APC). The volume in which this signal remains effective is unknown. This raises the possibility that cell volume may be the reason the SAC is weak, and chromosome segregation error-prone, in mammalian oocytes. Here, by a process of serial bisection, we analyzed the influence of oocyte volume on the ability of the SAC to inhibit bivalent segregation in meiosis I...
October 4, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28977935/overexpression-of-the-e2f-target-gene-cenpi-promotes-chromosome-instability-and-predicts-poor-prognosis-in-estrogen-receptor-positive-breast-cancer
#17
Pulari U Thangavelu, Cheng-Yu Lin, Srividya Vaidyanathan, Thu H M Nguyen, Eloise Dray, Pascal H G Duijf
During cell division, chromosome segregation is facilitated by the mitotic checkpoint, or spindle assembly checkpoint (SAC), which ensures correct kinetochore-microtubule attachments and prevents premature sister-chromatid separation. It is well established that misexpression of SAC components on the outer kinetochores promotes chromosome instability (CIN) and tumorigenesis. Here, we study the expression of CENP-I, a key component of the HIKM complex at the inner kinetochores, in breast cancer, including ductal, lobular, medullary and male breast carcinomas...
September 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/28974540/the-fission-yeast-nucleoporin-alm1-is-required-for-proteasomal-degradation-of-kinetochore-components
#18
Silvia Salas-Pino, Paola Gallardo, Ramón R Barrales, Sigurd Braun, Rafael R Daga
Kinetochores (KTs) are large multiprotein complexes that constitute the interface between centromeric chromatin and the mitotic spindle during chromosome segregation. In spite of their essential role, little is known about how centromeres and KTs are assembled and how their precise stoichiometry is regulated. In this study, we show that the nuclear pore basket component Alm1 is required to maintain both the proteasome and its anchor, Cut8, at the nuclear envelope, which in turn regulates proteostasis of certain inner KT components...
November 6, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/28943088/bubr1-promotes-bub3-dependent-apc-c-inhibition-during-spindle-assembly-checkpoint-signaling
#19
Katharina Overlack, Tanja Bange, Florian Weissmann, Alex C Faesen, Stefano Maffini, Ivana Primorac, Franziska Müller, Jan-Michael Peters, Andrea Musacchio
The spindle assembly checkpoint (SAC) prevents premature sister chromatid separation during mitosis. Phosphorylation of unattached kinetochores by the Mps1 kinase promotes recruitment of SAC machinery that catalyzes assembly of the SAC effector mitotic checkpoint complex (MCC). The SAC protein Bub3 is a phospho-amino acid adaptor that forms structurally related stable complexes with functionally distinct paralogs named Bub1 and BubR1. A short motif ("loop") of Bub1, but not the equivalent loop of BubR1, enhances binding of Bub3 to kinetochore phospho-targets...
October 9, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/28938551/overexpression-of-ubiquitin-specific-proteases-44-promotes-the-malignancy-of-glioma-by-stabilizing-tumor-promoter-securin
#20
Yongxiang Zou, Guanzhong Qiu, Lei Jiang, Zheng Cai, Wei Sun, Hongkang Hu, Chengyin Lu, Weilin Jin, Guohan Hu
Ubiquitin specific peptidase 44 (USP44) has been identified as an important component of spindle assemble checkpoint (SAC) to prevent the formation of aneuploidy. However, recent study raised a controversy about the effect of USP44 in tumor. Here, we first confirmed the intranuclear localization of USP44 by testing several specific antibodies to recognize endogenous USP44. Then, data from IHC and qRT-PCR assay indicated that the high expression of USP44 existed in high-grade glioma tissues and signified a poor prognosis...
August 29, 2017: Oncotarget
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