scholarly journals A TPR domain–containing N-terminal module of MPS1 is required for its kinetochore localization by Aurora B

2013 ◽  
Vol 201 (2) ◽  
pp. 217-231 ◽  
Author(s):  
Wilco Nijenhuis ◽  
Eleonore von Castelmur ◽  
Dene Littler ◽  
Valeria De Marco ◽  
Eelco Tromer ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Mitotic Spindle ◽  
Cell Cycle Progression ◽  
Mitotic Checkpoint ◽  
Binding Activity ◽  
Tetratricopeptide Repeat ◽  
Aurora B ◽  
Calponin Homology Domain ◽  
Cycle Progression ◽  
Tpr Domain

The mitotic checkpoint ensures correct chromosome segregation by delaying cell cycle progression until all kinetochores have attached to the mitotic spindle. In this paper, we show that the mitotic checkpoint kinase MPS1 contains an N-terminal localization module, organized in an N-terminal extension (NTE) and a tetratricopeptide repeat (TPR) domain, for which we have determined the crystal structure. Although the module was necessary for kinetochore localization of MPS1 and essential for the mitotic checkpoint, the predominant kinetochore binding activity resided within the NTE. MPS1 localization further required HEC1 and Aurora B activity. We show that MPS1 localization to kinetochores depended on the calponin homology domain of HEC1 but not on Aurora B–dependent phosphorylation of the HEC1 tail. Rather, the TPR domain was the critical mediator of Aurora B control over MPS1 localization, as its deletion rendered MPS1 localization insensitive to Aurora B inhibition. These data are consistent with a model in which Aurora B activity relieves a TPR-dependent inhibitory constraint on MPS1 localization.

scholarly journals Budding Yeast Bub2 Is Localized at Spindle Pole Bodies and Activates the Mitotic Checkpoint via a Different Pathway from Mad2

1999 ◽  
Vol 145 (5) ◽  
pp. 979-991 ◽  
Author(s):  
Roberta Fraschini ◽  
Elisa Formenti ◽  
Giovanna Lucchini ◽  
Simonetta Piatti
Keyword(s):  
Cell Cycle ◽  
Mitotic Spindle ◽  
Cell Cycle Progression ◽  
Budding Yeast ◽  
Spindle Pole Body ◽  
Mitotic Checkpoint ◽  
Spindle Pole ◽  
Cycle Progression ◽  
Spindle Pole Bodies

The mitotic checkpoint blocks cell cycle progression before anaphase in case of mistakes in the alignment of chromosomes on the mitotic spindle. In budding yeast, the Mad1, 2, 3, and Bub1, 2, 3 proteins mediate this arrest. Vertebrate homologues of Mad1, 2, 3, and Bub1, 3 bind to unattached kinetochores and prevent progression through mitosis by inhibiting Cdc20/APC-mediated proteolysis of anaphase inhibitors, like Pds1 and B-type cyclins. We investigated the role of Bub2 in budding yeast mitotic checkpoint. The following observations indicate that Bub2 and Mad1, 2 probably activate the checkpoint via different pathways: (a) unlike the other Mad and Bub proteins, Bub2 localizes at the spindle pole body (SPB) throughout the cell cycle; (b) the effect of concomitant lack of Mad1 or Mad2 and Bub2 is additive, since nocodazole-treated mad1 bub2 and mad2 bub2 double mutants rereplicate DNA more rapidly and efficiently than either single mutant; (c) cell cycle progression of bub2 cells in the presence of nocodazole requires the Cdc26 APC subunit, which, conversely, is not required for mad2 cells in the same conditions. Altogether, our data suggest that activation of the mitotic checkpoint blocks progression through mitosis by independent and partially redundant mechanisms.

scholarly journals Retinoblastoma Protein Enhances the Fidelity of Chromosome Segregation Mediated by hsHec1p

2000 ◽  
Vol 20 (10) ◽  
pp. 3529-3537 ◽  
Author(s):  
Lei Zheng ◽  
Yumay Chen ◽  
Daniel J. Riley ◽  
Phang-Lang Chen ◽  
Wen-Hwa Lee
Keyword(s):  
Dna Binding ◽  
Chromosome Segregation ◽  
Cell Cycle Progression ◽  
Retinoblastoma Protein ◽  
Binding Activity ◽  
Yeast Cells ◽  
Temperature Sensitive ◽  
Cycle Progression ◽  
Dna Binding Activity ◽  
M Phase

ABSTRACT Retinoblastoma protein (Rb) plays important roles in cell cycle progression and cellular differentiation. It may also participate in M phase events, although heretofore only circumstantial evidence has suggested such involvement. Here we show that Rb interacts, through an IxCxE motif and specifically during G2/M phase, with hsHec1p, a protein essential for proper chromosome segregation. The interaction between Rb and hsHec1p was reconstituted in a yeast strain in which human hsHEC1 rescues the null mutation of scHEC1. Expression of Rb reduced chromosome segregation errors fivefold in yeast cells sustained by a temperature-sensitive (ts) hshec1-113 allele and enhanced the ability of wild-type hsHec1p to suppress lethality caused by a ts smc1mutation. The interaction between Hec1p and Smc1p was important for the specific DNA-binding activity of Smc1p. Expression of Rb restored part of the inactivated function of hshec1-113p and thereby increased the DNA-binding activity of Smc1p. Rb thus increased the fidelity of chromosome segregation mediated by hsHec1p in a heterologous yeast system.

A highly conserved centrosomal kinase, AIR-1, is required for accurate cell cycle progression and segregation of developmental factors in Caenorhabditis elegans embryos

Development ◽  
1998 ◽  
Vol 125 (22) ◽  
pp. 4391-4402 ◽  
Author(s):  
J.M. Schumacher ◽  
N. Ashcroft ◽  
P.J. Donovan ◽  
A. Golden
Keyword(s):  
Chromosome Segregation ◽  
Mitotic Spindle ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Centrosomal Protein ◽  
C Elegans ◽  
Developmental Factors ◽  
Centrosome Separation ◽  
Spindle Dynamics ◽  
Bipolar Spindles

S. cerevisiae Ipl1, Drosophila Aurora, and the mammalian centrosomal protein IAK-1 define a new subfamily of serine/threonine kinases that regulate chromosome segregation and mitotic spindle dynamics. Mutations in ipl1 and aurora result in the generation of severely aneuploid cells and, in the case of aurora, monopolar spindles arising from a failure in centrosome separation. Here we show that a related, essential protein from C. elegans, AIR-1 (Aurora/Ipl1 related), is localized to mitotic centrosomes. Disruption of AIR-1 protein expression in C. elegans embryos results in severe aneuploidy and embryonic lethality. Unlike aurora mutants, this aneuploidy does not arise from a failure in centrosome separation. Bipolar spindles are formed in the absence of AIR-1, but they appear to be disorganized and are nucleated by abnormal-looking centrosomes. In addition to its requirement during mitosis, AIR-1 may regulate microtubule-based developmental processes as well. Our data suggests AIR-1 plays a role in P-granule segregation and the association of the germline factor PIE-1 with centrosomes.

scholarly journals Regulation of Aurora B Expression by the Bromodomain Protein Brd4

2009 ◽  
Vol 29 (18) ◽  
pp. 5094-5103 ◽  
Author(s):  
Jianxin You ◽  
Qing Li ◽  
Chong Wu ◽  
Jina Kim ◽  
Matthias Ottinger ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cancer Cells ◽  
Chromosome Segregation ◽  
Cell Cycle Progression ◽  
Cellular Proliferation ◽  
Regulatory Gene ◽  
Mitotic Catastrophe ◽  
Aurora B ◽  
Aurora B Kinase ◽  
Cycle Progression

ABSTRACT The bromodomain protein Brd4 plays critical roles in cellular proliferation and cell cycle progression. In this study, we investigated the involvement of Brd4 in cell cycle regulation and observed aberrant chromosome segregation and failures in cytokinesis in cancer cells as well as in primary keratinocytes in which Brd4 has been knocked down by RNA interference. Suppression of Brd4 protein levels in proliferating cells decreased Aurora B protein and transcript levels and abolished its chromosomal distribution. In contrast, exogenous Brd4 expression stimulated Aurora B promoter reporter activity and upregulated endogenous Aurora B expression. Aurora B kinase is a chromosomal passenger protein that is essential for chromosome segregation and cytokinesis. Either overexpression of Aurora B or its inactivation can induce defects in centrosome function, spindle assembly, chromosome alignment, and cytokinesis in various cancer cells. The impaired regulation of Aurora B expression in human cells by Brd4 knockdown or overexpression coincided with mitotic catastrophe and multinucleation that are typically observed when Aurora B is inactivated or overexpressed. Overall, our data suggest that Brd4 is essential for the maintenance of the cell cycle progression mediated at least in part through the control of transcription of the Aurora B kinase cell cycle regulatory gene.

scholarly journals Mps1 releases Mad1 from nuclear pores to ensure a robust mitotic checkpoint and accurate chromosome segregation

2019 ◽  
Author(s):  
Mariana Osswald ◽  
Sofia Cunha-Silva ◽  
Jana Goemann ◽  
João Barbosa ◽  
Luis M Santos ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Cell Cycle Progression ◽  
Spindle Assembly Checkpoint ◽  
Mitotic Checkpoint ◽  
Nuclear Pore ◽  
Nuclear Pore Complexes ◽  
Cycle Progression ◽  
Checkpoint Response ◽  
Pore Complexes

ABSTRACTThe strength of the Spindle Assembly Checkpoint (SAC) depends on the amount of the Mad1-C-Mad2 heterotetramer at kinetochores but also on its binding to Megator/Tpr at nuclear pore complexes (NPCs) during interphase. However, the molecular underpinnings controlling the spatiotemporal redistribution of Mad1-C-Mad2 as cells progress into mitosis remain elusive. Here, we show that Mps1-mediated phosphorylation of Megator/Tpr abolishes its interaction with Mad1 in vitro and in Drosophila cells. Timely activation of Mps1 during prophase triggers Mad1 release from NPCs, which we find to be required for competent kinetochore recruitment of Mad1-C-Mad2 and robust checkpoint response. Importantly, preventing Mad1 binding to Megator/Tpr rescues the fidelity of chromosome segregation and aneuploidy in larval neuroblasts of Drosophila mps1-null mutants. Our findings demonstrate that the subcellular localization of Mad1 is stringently coordinated with cell cycle progression by kinetochore-extrinsic activity of Mps1. This ensures that both NPCs in interphase and kinetochores in mitosis can generate anaphase inhibitors to efficiently preserve genomic stability.

scholarly journals Non‐redundant functions of H2A.Z.1 and H2A.Z.2 in chromosome segregation and cell cycle progression

EMBO Reports ◽  
2021 ◽  
Author(s):  
Raquel Sales‐Gil ◽  
Dorothee C Kommer ◽  
Ines J Castro ◽  
Hasnat A Amin ◽  
Veronica Vinciotti ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Chromosome Segregation ◽  
Cell Cycle Progression ◽  
Cycle Progression ◽  
Redundant Functions

The role of gamma-tubulin in mitotic spindle formation and cell cycle progression in Aspergillus nidulans

1997 ◽  
Vol 110 (5) ◽  
pp. 623-633 ◽  
Author(s):  
M.A. Martin ◽  
S.A. Osmani ◽  
B.R. Oakley
Keyword(s):  
Cell Cycle ◽  
Mitotic Spindle ◽  
Cell Cycle Progression ◽  
Spindle Pole ◽  
Microtubule Assembly ◽  
Cytoplasmic Microtubule ◽  
Cycle Progression ◽  
Spindle Microtubules ◽  
Gamma Tubulin

gamma-Tubulin has been hypothesized to be essential for the nucleation of the assembly of mitotic spindle microtubules, but some recent results suggest that this may not be the case. To clarify the role of gamma-tubulin in microtubule assembly and cell-cycle progression, we have developed a novel variation of the gene disruption/heterokaryon rescue technique of Aspergillus nidulans. We have used temperature-sensitive cell-cycle mutations to synchronize germlings carrying a gamma-tubulin disruption and observe the phenotypes caused by the disruption in the first cell cycle after germination. Our results indicate that gamma-tubulin is absolutely required for the assembly of mitotic spindle microtubules, a finding that supports the hypothesis that gamma-tubulin is involved in spindle microtubule nucleation. In the absence of functional gamma-tubulin, nuclei are blocked with condensed chromosomes for about the length of one cell cycle before chromatin decondenses without nuclear division. Our results indicate that gamma-tubulin is not essential for progression from G1 to G2, for entry into mitosis nor for spindle pole body replication. It is also not required for reactivity of spindle pole bodies with the MPM-2 antibody which recognizes a phosphoepitope important to mitotic spindle formation. Finally, it does not appear to be absolutely required for cytoplasmic microtubule assembly but may play a role in the formation of normal cytoplasmic microtubule arrays.

scholarly journals Mitotic spindle disassembly occurs via distinct subprocesses driven by the anaphase-promoting complex, Aurora B kinase, and kinesin-8

2010 ◽  
Vol 191 (4) ◽  
pp. 795-808 ◽  
Author(s):  
Jeffrey B. Woodruff ◽  
David G. Drubin ◽  
Georjana Barnes
Keyword(s):  
Mitotic Spindle ◽  
Cell Cycle Progression ◽  
Dynamic Structure ◽  
Aurora B ◽  
Anaphase Promoting Complex ◽  
Microtubule Depolymerization ◽  
Aurora B Kinase ◽  
Synthetic Lethal ◽  
Spindle Disassembly ◽  
Spindle Elongation

The mitotic spindle is a complex and dynamic structure. Although much has been learned about how spindles assemble and mediate chromosome segregation, how spindles rapidly and irreversibly disassemble during telophase is less clear. We used synthetic lethal screens in budding yeast to identify mutants defective in spindle disassembly. Real-time, live cell imaging analysis of spindle disassembly was performed on nine mutants defective in this process. Results of this analysis suggest that spindle disassembly is achieved by mechanistically distinct but functionally overlapping subprocesses: disengagement of the spindle halves, arrest of spindle elongation, and initiation of interpolar microtubule depolymerization. These subprocesses are largely governed by the anaphase-promoting complex, Aurora B kinase, and kinesin-8. Combinatorial inhibition of these subprocesses yielded cells with hyperstable spindle remnants and dramatic defects in cell cycle progression, establishing that rapid spindle disassembly is crucial for cell proliferation.

Meiotic cycle checkpoints in mammalian oocytes

Zygote ◽  
1994 ◽  
Vol 2 (4) ◽  
pp. 351-354 ◽  
Author(s):  
Josef Fulka ◽  
Judy Bradshaw ◽  
Robert Moor
Keyword(s):  
Chromosome Segregation ◽  
Cell Cycle Progression ◽  
Mitotic Cell ◽  
Mitotic Cell Cycle ◽  
Cycle Progression ◽  
Daughter Cells ◽  
Chromosomal Segregation ◽  
Nuclear Events ◽  
Last Stage ◽  
Meiotic Cycle

Recent Spectacular achievements have enabled the identification of key molecules responsible for mitotic cell cycle progression through the stages of G1, the gap before DNA replication; S, the phase of DNA synthesis; G2, the gap before chromosome segregation; and M, mitosis itself. The last stage has been most intensively studied, where MPE, maturation promotion factor, has been found responsible for the nuclear events associated with chromosomal segregation and the prodcution of two identical daughter cells (see Murray & Hunt, 1993).

Epigenetic dynamics across the cell cycle

2010 ◽  
Vol 48 ◽  
pp. 107-120 ◽  
Author(s):  
Tony Bou Kheir ◽  
Anders H. Lund
Keyword(s):  
Cell Cycle ◽  
Chromosome Segregation ◽  
Cell Cycle Progression ◽  
Current Knowledge ◽  
Chromatin Condensation ◽  
Chromatin Modifications ◽  
Cycle Progression ◽  
Daughter Cells ◽  
Mammalian Cell Cycle ◽  
Regulate Cell Cycle Progression

Progression of the mammalian cell cycle depends on correct timing and co-ordination of a series of events, which are managed by the cellular transcriptional machinery and epigenetic mechanisms governing genome accessibility. Epigenetic chromatin modifications are dynamic across the cell cycle, and are shown to influence and be influenced by cell-cycle progression. Chromatin modifiers regulate cell-cycle progression locally by controlling the expression of individual genes and globally by controlling chromatin condensation and chromosome segregation. The cell cycle, on the other hand, ensures a correct inheritance of epigenetic chromatin modifications to daughter cells. In this chapter, we summarize the current knowledge on the dynamics of epigenetic chromatin modifications during progression of the cell cycle.

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