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Spindle Assembly Checkpoint

Sophie Gay, Daniele Piccini, Christopher Bruhn, Sara Ricciardi, Paolo Soffientini, Walter Carotenuto, Stefano Biffo, Marco Foiani
Cell survival to replication stress depends on the activation of the Mec1ATR -Rad53 checkpoint response that protects the integrity of stalled forks and controls the origin firing program. Here we found that Mad2, a member of the spindle assembly checkpoint (SAC), contributes to efficient origin firing and to cell survival in response to replication stress. We show that Rad53 and Mad2 promote S-phase cyclin expression through different mechanisms: while Rad53 influences Clb5,6 degradation, Mad2 promotes their protein synthesis...
May 17, 2018: Molecular Cell
Xinran Liu, Yangkai Li, Lijing Meng, Xin-Yuan Liu, Anlin Peng, Yuchen Chen, Chengyu Liu, Hong Chen, Sheng Sun, Xiaoping Miao, Yu Zhang, Ling Zheng, Kun Huang
Proteins that bind to microtubule are important for cell cycle, and some of these proteins show oncogenic characteristics with mechanisms not fully understood. Herein we demonstrate overexpression of protein regulator of cytokinesis 1 (PRC1), a microtubule-associated regulator of mitosis, in human hepatocellular carcinoma (HCC). Moreover, upregulated PRC1 is associated with lower survival rates of HCC patients. Mechanistically, reducing PRC1 blocks mitotic exit of HCC cells at telophase in a spindle assembly checkpoint independent manner, and acts synergistically with microtubule-associated agents (MTAs) to suppress p53-wt or p53-null HCC cells in a p53- or p14ARF-dependent manner; while overexpressing PRC1 increases the resistance of HCC to taxol...
May 10, 2018: Cell Death & Disease
Zachary C Elmore, Rodrigo X Guillen, Kathleen L Gould
CK1 protein kinases contribute to multiple biological processes, but how they are tailored to function in compartmentalized signaling events is largely unknown. Hhp1 and Hhp2 (Hhp1/2) are the soluble CK1 family members in Schizosaccharomyces pombe. One of their functions is to inhibit the septation initiation network (SIN) during a mitotic checkpoint arrest. The SIN is assembled by Sid4 at spindle pole bodies (SPBs), and though Hhp1/2 co-localize there, it is not known how they are targeted there nor if their SPB localization is required for SIN inhibition...
May 9, 2018: Molecular Biology of the Cell
Beryl Augustine, Cheen Fei Chin, Foong May Yeong
Mitotic spindle dynamics are regulated during the cell cycle by microtubule motor proteins. One such protein is Kip2p, a plus-ended motor that regulates the polymerization and stability of cytoplasmic microtubules (cMTs). Kip2p levels are regulated during the cell cycle and its overexpression leads to the formation of hyper-elongated cMTs. To investigate the significance of varying Kip2p levels during the cell cycle and the hyper-elongated cMTs, we overexpressed KIP2 in G1 phase and examined the effects on the separation of spindle pole bodies (SPBs) and chromosome segregation...
May 8, 2018: Journal of Cell Science
Mark D Gurden, Simon J Anderhub, Amir Faisal, Spiros Linardopoulos
Accurate chromosome segregation is dependent on the spindle assembly checkpoint (SAC). In current models, the key direct role of Aurora B in the SAC has been suggested to be to promote rapid kinetochore localisation of MPS1, allowing MPS1 to generate the checkpoint signal. However, Aurora B is also thought to play an indirect role in the SAC through the destabilisation of kinetochore-microtubule (KT-MT) attachments. Here, we demonstrate that Aurora B activity is not required for the kinetochore recruitment of the majority of SAC proteins...
April 13, 2018: Oncotarget
Feng Li, Hyeung Kim, Zhejian Ji, Tianpeng Zhang, Bohong Chen, Yuanlong Ge, Yang Hu, Xuyang Feng, Xin Han, Huimin Xu, Youwei Zhang, Hongtao Yu, Dan Liu, Wenbin Ma, Zhou Songyang
Telomeres and telomere-binding proteins form complex secondary nucleoprotein structures that are critical for genome integrity but can present serious challenges during telomere DNA replication. It remains unclear how telomere replication stress is resolved during S phase. Here, we show that the BUB3-BUB1 complex, a component in spindle assembly checkpoint, binds to telomeres during S phase and promotes telomere DNA replication. Loss of the BUB3-BUB1 complex results in telomere replication defects, including fragile and shortened telomeres...
May 3, 2018: Molecular Cell
Mohamed Bourmoum, Ricardo Charles, Audrey Claing
Sister chromatid cohesion, ensured by the protein complex, cohesin, is crucial for the establishment of stable bipolar attachments of chromosomes to the spindle microtubules and their faithful segregation. Here, we demonstrate that the GTPase ARF6 prevents the premature loss of sister chromatid cohesion. During mitosis, ARF6 depleted cells normally completed chromosome congression. However, at the metaphase plate, chromosomes failed to establish stable kinetochore-microtubule attachments because of the impaired cohesion at centromeres...
May 3, 2018: Journal of Cell Science
Danica Drpic, Ana C Almeida, Paulo Aguiar, Fioranna Renda, Joana Damas, Harris A Lewin, Denis M Larkin, Alexey Khodjakov, Helder Maiato
Chromosome missegregation during mitosis or meiosis is a hallmark of cancer and the main cause of prenatal death in humans. The gain or loss of specific chromosomes is thought to be random, with cell viability being essentially determined by selection. Several established pathways including centrosome amplification, sister-chromatid cohesion defects, or a compromised spindle assembly checkpoint can lead to chromosome missegregation. However, how specific intrinsic features of the kinetochore-the critical chromosomal interface with spindle microtubules-impact chromosome segregation remains poorly understood...
April 20, 2018: Current Biology: CB
Abigail R Gerhold, Vincent Poupart, Jean-Claude Labbé, Paul S Maddox
The spindle assembly checkpoint (SAC) is a conserved mitotic regulator that preserves genome stability by monitoring kinetochore-microtubule attachments and blocking anaphase onset until chromosome bi-orientation is achieved. Despite its central role in maintaining mitotic fidelity, the ability of the SAC to delay mitotic exit in the presence of kinetochore-microtubule attachment defects (SAC "strength") appears to vary widely. How different cellular aspects drive this variation remains largely unknown...
April 24, 2018: Molecular Biology of the Cell
Agnieszka Skowyra, Lindsey A Allan, Adrian T Saurin, Paul R Clarke
Faithful chromosome segregation during mitosis depends on the spindle assembly checkpoint (SAC), which delays progression through mitosis until every chromosome has stably attached to spindle microtubules via the kinetochore. We show here that the deubiquitinase USP9X strengthens the SAC by antagonizing the turnover of the mitotic checkpoint complex produced at unattached kinetochores. USP9X thereby opposes activation of anaphase-promoting complex/cyclosome (APC/C) and specifically inhibits the mitotic degradation of SAC-controlled APC/C substrates...
April 17, 2018: Cell Reports
Wenshuang Wu, Feng Liu, Anping Su, Yanping Gong, Wanjun Zhao, Yang Liu, Haoyu Ye, Jingqiang Zhu
Millepachine (MIL) is a bioactive natural product that shows great potential for cancer treatment. Previous studies showed that MIL was a novel cancer drug candidate with a special structure. To provide reference for the research and development of MIL, we further investigated the mechanism of MIL inducing G2/M arrest and found MIL disrupted spindle assembly in tumor cells. In this study, we investigated the disrupting spindle assembly effects of MIL with a focus on its potential mechanism of action. First, we indicated that MIL did not inhibit microtubule polymerization from the results of in-vivo microtubule nucleation assay and microtubule polymerization in-vitro assay but delayed this process by inhibiting the production of ATP in tumor cells...
June 2018: Anti-cancer Drugs
Martin R Gill, Paul J Jarman, Swagata Halder, Michael G Walker, Hiwa K Saeed, Jim A Thomas, Carl Smythe, Kristijan Ramadan, Katherine A Vallis
Substitutionally inert ruthenium(ii) polypyridyl complexes have been developed as DNA intercalating agents yet cellular DNA damage responses to this binding modality are largely unexplored. Here, we show the nuclear-targeting complex [Ru(phen)2 (tpphz)]2+ (phen = 1,10-phenanthroline, tpphz = tetrapyridophenazine) generates rapid and pronounced stalling of replication fork progression in p53-deficient human oesophageal cancer cells. In response, replication stress and double-strand break (DSB) DNA damage response (DDR) pathways are activated and cell proliferation is inhibited by growth arrest...
January 28, 2018: Chemical Science
Taryne Chong, Amila Sarac, Cindy Q Yao, Linda Liao, Nicola Lyttle, Paul C Boutros, John M S Bartlett, Melanie Spears
BACKGROUND: Ovarian cancer is the leading gynecologic cancer diagnosed in North America and because related symptoms are not disease specific, this often leads to late detection, an advanced disease state, and the need for chemotherapy. Ovarian cancer is frequently sensitive to chemotherapy at diagnosis but rapid development of drug resistance leads to disease progression and ultimately death in the majority of patients. RESULTS: We have generated paclitaxel resistant ovarian cell lines from their corresponding native cell lines to determine driver mechanisms of drug resistance using gene expression arrays...
April 4, 2018: Journal of Ovarian Research
Prajakta Varadkar, Kazuyo Takeda, Brenton McCright
Chromosomes must be reliably and uniformly segregated into daughter cells during mitotic cell division. Fidelity of chromosomal segregation is controlled by multiple mechanisms that include the Spindle Assembly Checkpoint (SAC). The SAC is part of a complex feedback system that is responsible for prevention of a cell progress through mitosis unless all chromosomal kinetochores have attached to spindle microtubules. Chromosomal lagging and abnormal chromosome segregation is an indicator of dysfunctional cell cycle control checkpoints and can be used to measure the genomic stability of dividing cells...
March 14, 2018: Journal of Visualized Experiments: JoVE
Thibault Courtheoux, Alghassimou Diallo, Arun Prasath Damodaran, David Reboutier, Erwan Watrin, Claude Prigent
During the prometaphase stage of mitosis, the cell builds a bipolar spindle of microtubules that mechanically segregates sister chromatids for two daughter cells in anaphase. The spindle assembly checkpoint (SAC) is a quality control mechanism that monitors proper attachment of microtubules to chromosome kinetochores during prometaphase. Segregation occurs only when each chromosome is bi-oriented with each kinetochore pair attached to microtubules emanating from opposite spindle poles. Overexpression of the protein kinase Aurora A is a feature of various cancers and is thought to enable tumour cells to bypass the SAC leading to aneuploidy...
March 19, 2018: Journal of Cell Science
Monika Raab, Mourad Sanhaji, Yves Matthess, Albrecht Hörlin, Ioana Lorenz, Christina Dötsch, Nils Habbe, Oliver Waidmann, Elisabeth Kurunci-Csacsko, Ron Firestein, Sven Becker, Klaus Strebhardt
The spindle assembly checkpoint (SAC) acts as a molecular safeguard in ensuring faithful chromosome transmission during mitosis, which is regulated by a complex interplay between phosphatases and kinases including PLK1. Adenomatous polyposis coli (APC) germline mutations cause aneuploidy and are responsible for familial adenomatous polyposis (FAP). Here we study the role of PLK1 in colon cancer cells with chromosomal instability promoted by APC truncation (APC-ΔC). The expression of APC-ΔC in colon cells reduces the accumulation of mitotic cells upon PLK1 inhibition, accelerates mitotic exit and increases the survival of cells with enhanced chromosomal abnormalities...
March 16, 2018: Nature Communications
Hanako Hayashi, Bungo Akiyoshi
Kinetoplastids have a nucleus that contains the nuclear genome and a kinetoplast that contains the mitochondrial genome. These single-copy organelles must be duplicated and segregated faithfully to daughter cells at each cell division. In Trypanosoma brucei , although duplication of both organelles starts around the same time, segregation of the kinetoplast precedes that of the nucleus. Cytokinesis subsequently takes place so that daughter cells inherit a single copy of each organelle. Very little is known about the molecular mechanism that governs the timing of these events...
March 23, 2018: Biology Open
Christine C Lee, Bing Li, Hongtao Yu, Michael J Matunis
The Anaphase Promoting Complex/Cyclosome (APC/C) is a ubiquitin E3 ligase that functions as the gatekeeper to mitotic exit. APC/C activity is controlled by an interplay of multiple pathways during mitosis, including the spindle assembly checkpoint (SAC), that are not yet fully understood. Here, we show that sumoylation of the APC4 subunit of the APC/C peaks during mitosis and is critical for timely APC/C activation and anaphase onset. We have also identified a functionally important SUMO interacting motif in the cullin-homology domain of APC2 located near the APC4 sumoylation sites and APC/C catalytic core...
March 8, 2018: ELife
Guillaume Combes, Helena Barysz, Chantal Garand, Luciano Gama Braga, Ibrahim Alharbi, Philippe Thebault, Luc Murakami, Dominic P Bryne, Stasa Stankovic, Patrick A Eyers, Victor M Bolanos-Garcia, William C Earnshaw, John Maciejowski, Prasad V Jallepalli, Sabine Elowe
Monopolar spindle 1 (Mps1) is a conserved apical kinase in the spindle assembly checkpoint (SAC) that ensures accurate segregation of chromosomes during mitosis. Mps1 undergoes extensive auto- and transphosphorylation, but the regulatory and functional consequences of these modifications remain unclear. Recent findings highlight the importance of intermolecular interactions between the N-terminal extension (NTE) of Mps1 and the Hec1 subunit of the NDC80 complex, which control Mps1 localization at kinetochores and activation of the SAC...
March 19, 2018: Current Biology: CB
Caroline Kolenda, Jennifer Ortiz, Marina Pelzl, Sarina Norell, Verena Schmeiser, Johannes Lechner
Kinetochores that are not attached to microtubules prevent chromosome missegregation via the spindle assembly checkpoint. We show that they also promote their own capturing. Similar to what governs the localization of spindle assembly checkpoint proteins, the phosphorylation of Spc105 by Mps1 allows unattached kinetochores to sequester Stu1 in cooperation with Slk19. The withdrawal of Stu1, a CLASP essential for spindle integrity, from microtubules and attached kinetochores disrupts the organization of the spindle and thus allows the enhanced formation of dynamic random microtubules that span the nucleus and are ideal to capture unattached kinetochores...
February 28, 2018: Nature Communications
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