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Spindle checkpoint

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 12, 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...
February 20, 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
Ksenia Krupina, Charlotte Kleiss, Sushil Awal, Irene Rodriguez-Hernandez, Victoria Sanz-Moreno, Izabela Sumara
Defects in mitosis can lead to aneuploidy, which is a common feature of human cancers. Spindle Assembly Checkpoint (SAC) controls fidelity of chromosome segregation in mitosis to prevent aneuploidy. The ubiquitin receptor protein Ubiquitin Associated and SH3 Domain Containing B (UBASH3B) was recently found to control SAC silencing and faithful chromosome segregation by relocalizing Aurora B kinase to the mitotic microtubules. Accordingly, loss and gain of function of UBASH3B have strong effects on mitotic progression...
2018: Molecular & Cellular Oncology
Nando Cervone, Rosa Della Monica, Angela Flavia Serpico, Cinzia Vetrei, Mario Scaraglio, Roberta Visconti, Domenico Grieco
Progression through mitosis, the cell cycle phase deputed to segregate replicated chromosomes, is granted by a protein phosphorylation wave that follows an activation-inactivation cycle of cyclin B-dependent kinase (Cdk) 1, the major mitosis-promoting enzyme. To ensure correct chromosome segregation, the safeguard mechanism spindle assembly checkpoint (SAC) delays Cdk1 inactivation by preventing cyclin B degradation until mitotic spindle assembly. At the end of mitosis, reversal of bulk mitotic protein phosphorylation, downstream Cdk1 inactivation, is required to complete mitosis and crucially relies on the activity of major protein phosphatases like PP2A...
January 26, 2018: Oncotarget
Mohammed A Amin, Richard J McKenney, Dileep Varma
Chromosome alignment and segregation during mitosis require kinetochore-microtubule (kMT) attachments that are mediated by the molecular motor dynein and the kMT-binding complex Ndc80. The Rod-ZW10-Zwilch (RZZ) complex is central to this coordination, as it has an important role in dynein recruitment and has recently been reported to have a key function in the regulation of stable kMT attachments in Caenorhabditis elegans, besides its role in activating the spindle assembly checkpoint (SAC). However, the mechanism by which these protein complexes control kMT attachments to drive chromosome motility during early mitosis is still unclear...
February 23, 2018: Journal of Biological Chemistry
Jan G Ruppert, Kumiko Samejima, Melpomeni Platani, Oscar Molina, Hiroshi Kimura, A Arockia Jeyaprakash, Shinya Ohta, William C Earnshaw
The chromosomal passenger complex (CPC) is directed to centromeres during mitosis via binding to H3T3ph and Sgo1. Whether and how heterochromatin protein 1α (HP1α) influences CPC localisation and function during mitotic entry is less clear. Here, we alter HP1α dynamics by fusing it to a CENP-B DNA-binding domain. Tethered HP1 strongly recruits the CPC, destabilising kinetochore-microtubule interactions and activating the spindle assembly checkpoint. During mitotic exit, the tethered HP1 traps active CPC at centromeres...
February 21, 2018: EMBO Journal
Hanning Ying, Zhiyao Xu, Mingming Chen, Senjun Zhou, Xiao Liang, Xiujun Cai
Introduction: Zwint, a centromere-complex component required for the mitotic spindle checkpoint, has been reported to be overexpressed in different human cancers, but it has not been studied in human hepatocellular carcinoma (HCC). Materials and methods: The role of Zwint in hepatocellular carcinoma cell proliferation capacities was evaluated by using cell counting kit-8 (CCK8), flow cytometry, clone formation and tumor formation assay in nude mice. Western blot analysis and qPCR assay were performed to assess Zwint interacting with cell-cycle-related proteins...
2018: OncoTargets and Therapy
Danielle Sitry-Shevah, Sharon Kaisari, Adar Teichner, Shirly Miniowitz-Shemtov, Avram Hershko
The mitotic checkpoint system ensures the fidelity of chromosome segregation in mitosis by preventing premature initiation of anaphase until correct bipolar attachment of chromosomes to the mitotic spindle is reached. It promotes the assembly of a mitotic checkpoint complex (MCC), composed of BubR1, Bub3, Cdc20, and Mad2, which inhibits the activity of the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase. When the checkpoint is satisfied, anaphase is initiated by the disassembly of MCC. Previous studies indicated that the dissociation of APC/C-bound MCC requires ubiquitylation and suggested that the target of ubiquitylation is the Cdc20 component of MCC...
February 5, 2018: Proceedings of the National Academy of Sciences of the United States of America
Hoi Tang Ma, Randy Y C Poon
The spindle assembly checkpoint (SAC) prevents premature segregation of chromosomes during mitosis. This process requires structural remodeling of MAD2 from O-MAD2 to C-MAD2 conformation. After the checkpoint is satisfied, C-MAD2 is reverted to O-MAD2 to allow anaphase-promoting complex/cyclosome (APC/C) to trigger anaphase. Recently, the AAA+-ATPase TRIP13 was shown to act in concert with p31comet to catalyze C- to O-MAD2. Paradoxically, although C-MAD2 is present in TRIP13-deficient cells, the SAC cannot be activated...
February 6, 2018: Cell Reports
Jonne A Raaijmakers, Roy G H P van Heesbeen, Vincent A Blomen, Louise M E Janssen, Ferdy van Diemen, Thijn R Brummelkamp, René H Medema
The spindle assembly checkpoint (SAC) ensures faithful segregation of chromosomes. Although most mammalian cell types depend on the SAC for viability, we found that human HAP1 cells can grow SAC independently. We generated MAD1- and MAD2-deficient cells and mutagenized them to identify synthetic lethal interactions, revealing that chromosome congression factors become essential upon SAC deficiency. Besides expected hits, we also found that BUB1 becomes essential in SAC-deficient cells. We found that the BUB1 C terminus regulates alignment as well as recruitment of CENPF...
February 6, 2018: Cell Reports
Xingkang Wu, Zhenyu Li, Yuemao Shen
BACKGROUND: Mitosis, the most dramatic event in the cell cycle, involves the reorganization of virtually all cellular components. Antimitotic agents are useful for dissecting the mechanism of this reorganization. Previously, we found that the small molecule CS1 accumulates cells in G2/M phase [1], but the mechanism of its action remains unknown. METHODS: Cell cycle analysis, live cell imaging and nuclear staining were used. Chromosomal morphology was detected by chromosome spreading...
January 30, 2018: Biochimica et Biophysica Acta
Dang Wu, Lepeng Wang, Yanhong Yang, Jin Huang, Yuhua Hu, Yongwei Shu, Jingyu Zhang, Jing Zheng
Mitotic arrest deficient-like-1 (MAD2, also known as MAD2L1) is thought to be an important spindle assembly checkpoint protein, which ensures accurate chromosome segregation and is closely associated with poor prognosis in many cancer. As a MAD2 binding protein, p31comet counteracts the function of MAD2 and leads to mitotic checkpoint silence. In this study, we explore the function of MAD2-p31comet axis in malignant glioma cells. Our results showed that disruption of MAD2-p31comet axis by MAD2 knockdown or p31comet overexpression suppressed cell proliferation, survival and migration of glioma, indicating that MAD2-p31comet axis is required for maintaining glioma cells malignancy...
February 2, 2018: Biochemical and Biophysical Research Communications
Özge Saatci, Simone Borgoni, Özge Akbulut, Selvi Durmuş, Umar Raza, Erol Eyüpoğlu, Can Alkan, Aytekin Akyol, Özgür Kütük, Stefan Wiemann, Özgür Şahin
Trastuzumab-refractory, HER2 (human epidermal growth factor receptor 2)-positive breast cancer is commonly treated with trastuzumab emtansine (T-DM1), an antibody-drug conjugate of trastuzumab and the microtubule-targeting agent, DM1. However, drug response reduces greatly over time due to acquisition of resistance whose molecular mechanisms are mostly unknown. Here, we uncovered a novel mechanism of resistance against T-DM1 by combining whole transcriptome sequencing (RNA-Seq), proteomics and a targeted small interfering RNA (siRNA) sensitization screen for molecular level analysis of acquired and de novo T-DM1-resistant models of HER2-overexpressing breast cancer...
February 2, 2018: Oncogene
Kai Chen, Wenxiu Duan, Qianqian Han, Xuan Sun, Wenqian Li, Shuangyun Hu, Jiajia Wan, Jiang Wu, Yushu Ge, Dan Liu
Protein kinase monopolar spindle 1 plays an important role in spindle assembly checkpoint at the onset of mitosis. Over expression of MPS1 correlated with a wide range of human tumors makes it an attractive target for finding an effective and specific inhibitor. In this work, we performed molecular dynamics simulations of protein MPS1 itself as well as protein bound systems with the inhibitor and natural substrate based on crystal structures. The reported orally bioavailable 1h-pyrrolo [3,2-c] pyridine inhibitors of MPS1 maintained stable binding in the catalytic site while natural substrate ATP could not stay...
January 30, 2018: Journal of Biomolecular Structure & Dynamics
K L Thu, J Silvester, M J Elliott, W Ba-Alawi, M H Duncan, A C Elia, A S Mer, P Smirnov, Z Safikhani, B Haibe-Kains, T W Mak, D W Cescon
TTK protein kinase (TTK), also known as Monopolar spindle 1 (MPS1), is a key regulator of the spindle assembly checkpoint (SAC), which functions to maintain genomic integrity. TTK has emerged as a promising therapeutic target in human cancers, including triple-negative breast cancer (TNBC). Several TTK inhibitors (TTKis) are being evaluated in clinical trials, and an understanding of the mechanisms mediating TTKi sensitivity and resistance could inform the successful development of this class of agents. We evaluated the cellular effects of the potent clinical TTKi CFI-402257 in TNBC models...
January 29, 2018: Proceedings of the National Academy of Sciences of the United States of America
Markus Alexander Grohme, Siegfried Schloissnig, Andrei Rozanski, Martin Pippel, George Robert Young, Sylke Winkler, Holger Brandl, Ian Henry, Andreas Dahl, Sean Powell, Michael Hiller, Eugene Myers, Jochen Christian Rink
The planarian Schmidtea mediterranea is an important model for stem cell research and regeneration, but adequate genome resources for this species have been lacking. Here we report a highly contiguous genome assembly of S. mediterranea, using long-read sequencing and a de novo assembler (MARVEL) enhanced for low-complexity reads. The S. mediterranea genome is highly polymorphic and repetitive, and harbours a novel class of giant retroelements. Furthermore, the genome assembly lacks a number of highly conserved genes, including critical components of the mitotic spindle assembly checkpoint, but planarians maintain checkpoint function...
January 24, 2018: Nature
Eleni Petsalaki, Maria Dandoulaki, George Zachos
The mitotic spindle checkpoint delays anaphase onset in the presence of unattached kinetochores, and efficient checkpoint signaling requires kinetochore localization of the Rod-ZW10-Zwilch (RZZ) complex. In the present study, we show that human Chmp4c, a protein involved in membrane remodeling, localizes to kinetochores in prometaphase but is reduced in chromosomes aligned at the metaphase plate. Chmp4c promotes stable kinetochore-microtubule attachments and is required for proper mitotic progression, faithful chromosome alignment, and segregation...
January 23, 2018: Journal of Cell Biology
Yajuan Lu, Sen Li, Zhaokang Cui, Xiaoxin Dai, Mianqun Zhang, Yilong Miao, Changyin Zhou, Xianghong Ou, Bo Xiong
Esco1 has been reported to function as a cohesion establishment factor that mediates chromosome cohesion and segregation in mitotic cells. However, its exact roles in meiosis have not been clearly defined. Here, we document that Esco1 is expressed and localized to both the nucleus and cytoplasm during mouse oocyte meiotic maturation. Depletion of Esco1 by siRNA microinjection causes the meiotic progression arrest with a severe spindle abnormality and chromosome misalignment, which is coupled with a higher incidence of the erroneous kinetochore-microtubule attachments and activation of spindle assembly checkpoint...
January 19, 2018: Nucleic Acids Research
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