scholarly journals Mps1 regulates spindle morphology through MCRS1 to promote chromosome alignment

2019 ◽  
Vol 30 (9) ◽  
pp. 1060-1068 ◽  
Author(s):  
Hongdan Yang ◽  
Fengxia Zhang ◽  
Ching-Jung Huang ◽  
Jun Liao ◽  
Ying Han ◽  
...  
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Underlying Mechanism ◽  
Genome Maintenance ◽  
Microtubule Attachment ◽  
Downstream Effectors ◽  
Chromosome Alignment ◽  
Assembly Factor ◽  
Spindle Microtubules

Accurate partitioning of chromosomes during mitosis is essential for genetic stability and requires the assembly of the dynamic mitotic spindle and proper kinetochore–microtubule attachment. The spindle assembly checkpoint (SAC) monitors the incompleteness and errors in kinetochore–microtubule attachment and delays anaphase. The SAC kinase Mps1 regulates the recruitment of downstream effectors to unattached kinetochores. Mps1 also actively promotes chromosome alignment during metaphase, but the underlying mechanism is not completely understood. Here, we show that Mps1 regulates chromosome alignment through MCRS1, a spindle assembly factor that controls the dynamics of the minus end of kinetochore microtubules. Mps1 binds and phosphorylates MCRS1. This mechanism enables KIF2A localization to the minus end of spindle microtubules. Thus, our study reveals a novel role of Mps1 in regulating the dynamics of the minus end of microtubules and expands the functions of Mps1 in genome maintenance.

scholarly journals DNA damage responses in mammalian oocytes

Reproduction ◽  
2016 ◽  
Vol 152 (1) ◽  
pp. R15-R22 ◽  
Author(s):  
Josie K Collins ◽  
Keith T Jones
Keyword(s):  
Dna Damage ◽  
Spindle Assembly Checkpoint ◽  
Germinal Vesicle ◽  
Spindle Assembly ◽  
Stages Of Growth ◽  
Microtubule Attachment ◽  
Dna Damage Responses ◽  
Chromosome Attachment ◽  
Spindle Microtubules ◽  
Meiosis I

DNA damage acquired during meiosis can lead to infertility and miscarriage. Hence, it should be important for an oocyte to be able to detect and respond to such events in order to make a healthy egg. Here, the strategies taken by oocytes during their stages of growth to respond to DNA damaging events are reviewed. In particular, recent evidence of a novel pathway in fully grown oocytes helps prevent the formation of mature eggs with DNA damage. It has been found that fully grown germinal vesicle stage oocytes that have been DNA damaged do not arrest at this point in meiosis, but instead undergo meiotic resumption and stall during the first meiotic division. The Spindle Assembly Checkpoint, which is a well-known mitotic pathway employed by somatic cells to monitor chromosome attachment to spindle microtubules, appears to be utilised by oocytes also to respond to DNA damage. As such maturing oocytes are arrested at metaphase I due to an active Spindle Assembly Checkpoint. This is surprising given this checkpoint has been previously studied in oocytes and considered to be weak and ineffectual because of its poor ability to be activated in response to microtubule attachment errors. Therefore, the involvement of the Spindle Assembly Checkpoint in DNA damage responses of mature oocytes during meiosis I uncovers a novel second function for this ubiquitous cellular checkpoint.

scholarly journals Knl1 participates in spindle assembly checkpoint signaling in maize

2021 ◽  
Vol 118 (20) ◽  
pp. e2022357118
Author(s):  
Handong Su ◽  
Yang Liu ◽  
Chunhui Wang ◽  
Yalin Liu ◽  
Chao Feng ◽  
...  
Keyword(s):  
Cell Division ◽  
Evolutionary History ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Helical Conformation ◽  
Evolutionary Patterns ◽  
Checkpoint Signaling ◽  
Microtubule Attachment ◽  
Tpr Domain

The Knl1-Mis12-Ndc80 (KMN) network is an essential component of the kinetochore–microtubule attachment interface, which is required for genomic stability in eukaryotes. However, little is known about plant Knl1 proteins because of their complex evolutionary history. Here, we cloned the Knl1 homolog from maize (Zea mays) and confirmed it as a constitutive central kinetochore component. Functional assays demonstrated their conserved role in chromosomal congression and segregation during nuclear division, thus causing defective cell division during kernel development when Knl1 transcript was depleted. A 145 aa region in the middle of maize Knl1, that did not involve the MELT repeats, was associated with the interaction of spindle assembly checkpoint (SAC) components Bub1/Mad3 family proteins 1 and 2 (Bmf1/2) but not with the Bmf3 protein. They may form a helical conformation with a hydrophobic interface with the TPR domain of Bmf1/2, which is similar to that of vertebrates. However, this region detected in monocots shows extensive divergence in eudicots, suggesting that distinct modes of the SAC to kinetochore connection are present within plant lineages. These findings elucidate the conserved role of the KMN network in cell division and a striking dynamic of evolutionary patterns in the SAC signaling and kinetochore network.

scholarly journals The equatorial position of the metaphase plate ensures symmetric cell divisions

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Chia Huei Tan ◽  
Ivana Gasic ◽  
Sabina P Huber-Reggi ◽  
Damian Dudka ◽  
Marin Barisic ◽  
...  
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Metaphase Plate ◽  
Spindle Assembly ◽  
Equatorial Position ◽  
Asymmetric Cell Divisions ◽  
Daughter Cells ◽  
Cell Divisions ◽  
Microtubule Stability ◽  
Chromosome Alignment ◽  
Metazoan Cell

Chromosome alignment in the middle of the bipolar spindle is a hallmark of metazoan cell divisions. When we offset the metaphase plate position by creating an asymmetric centriole distribution on each pole, we find that metaphase plates relocate to the middle of the spindle before anaphase. The spindle assembly checkpoint enables this centering mechanism by providing cells enough time to correct metaphase plate position. The checkpoint responds to unstable kinetochore–microtubule attachments resulting from an imbalance in microtubule stability between the two half-spindles in cells with an asymmetric centriole distribution. Inactivation of the checkpoint prior to metaphase plate centering leads to asymmetric cell divisions and daughter cells of unequal size; in contrast, if the checkpoint is inactivated after the metaphase plate has centered its position, symmetric cell divisions ensue. This indicates that the equatorial position of the metaphase plate is essential for symmetric cell divisions.

Too MAD or not MAD enough: The duplicitous role of the spindle assembly checkpoint protein MAD2 in cancer

2020 ◽  
Vol 469 ◽  
pp. 11-21 ◽  
Author(s):  
Mark Bates ◽  
Fiona Furlong ◽  
Michael F. Gallagher ◽  
Cathy D. Spillane ◽  
Amanda McCann ◽  
...  
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Checkpoint Protein ◽  
Spindle Assembly Checkpoint Protein

scholarly journals Role of the Mad2 Dimerization Interface in the Spindle Assembly Checkpoint Independent of Kinetochores

2012 ◽  
Vol 22 (20) ◽  
pp. 1900-1908 ◽  
Author(s):  
Luca Mariani ◽  
Elena Chiroli ◽  
Luigi Nezi ◽  
Heiko Muller ◽  
Simonetta Piatti ◽  
...  
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Dimerization Interface

Evidence that the spindle assembly checkpoint does not regulate APCFzy activity in Drosophila female meiosis

Genome ◽  
2012 ◽  
Vol 55 (1) ◽  
pp. 63-67 ◽  
Author(s):  
Osamah Batiha ◽  
Andrew Swan
Keyword(s):  
Chromosome Segregation ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Cyclin B ◽  
Meiotic Spindle ◽  
Loss Of Function ◽  
Female Meiosis ◽  
Chromosome Attachment ◽  
Spindle Microtubules ◽  
Made In

The spindle assembly checkpoint (SAC) plays an important role in mitotic cells to sense improper chromosome attachment to spindle microtubules and to inhibit APCFzy-dependent destruction of cyclin B and Securin; consequent initiation of anaphase until correct attachments are made. In Drosophila , SAC genes have been found to play a role in ensuring proper chromosome segregation in meiosis, possibly reflecting a similar role for the SAC in APCFzy inhibition during meiosis. We found that loss of function mutations in SAC genes, Mad2, zwilch, and mps1, do not lead to the predicted rise in APCFzy-dependent degradation of cyclin B either globally throughout the egg or locally on the meiotic spindle. Further, the SAC is not responsible for the inability of APCFzy to target cyclin B and promote anaphase in metaphase II arrested eggs from cort mutant females. Our findings support the argument that SAC proteins play checkpoint independent roles in Drosophila female meiosis and that other mechanisms must function to control APC activity.

scholarly journals Cdk1 and Plk1 mediate a CLASP2 phospho-switch that stabilizes kinetochore–microtubule attachments

2012 ◽  
Vol 199 (2) ◽  
pp. 285-301 ◽  
Author(s):  
Ana R.R. Maia ◽  
Zaira Garcia ◽  
Lilian Kabeche ◽  
Marin Barisic ◽  
Stefano Maffini ◽  
...  
Keyword(s):  
Chromosome Segregation ◽  
Spindle Assembly Checkpoint ◽  
Regulatory Mechanism ◽  
Stable Condition ◽  
Spindle Assembly ◽  
Chromosome Alignment ◽  
Chromosome Movements

Accurate chromosome segregation during mitosis relies on a dynamic kinetochore (KT)–microtubule (MT) interface that switches from a labile to a stable condition in response to correct MT attachments. This transition is essential to satisfy the spindle-assembly checkpoint (SAC) and couple MT-generated force with chromosome movements, but the underlying regulatory mechanism remains unclear. In this study, we show that during mitosis the MT- and KT-associated protein CLASP2 is progressively and distinctively phosphorylated by Cdk1 and Plk1 kinases, concomitant with the establishment of KT–MT attachments. CLASP2 S1234 was phosphorylated by Cdk1, which primed CLASP2 for association with Plk1. Plk1 recruitment to KTs was enhanced by CLASP2 phosphorylation on S1234. This was specifically required to stabilize KT–MT attachments important for chromosome alignment and to coordinate KT and non-KT MT dynamics necessary to maintain spindle bipolarity. CLASP2 C-terminal phosphorylation by Plk1 was also required for chromosome alignment and timely satisfaction of the SAC. We propose that Cdk1 and Plk1 mediate a fine CLASP2 “phospho-switch” that temporally regulates KT–MT attachment stability.

scholarly journals Interactions between N-Terminal Modules in MPS1 Enable Spindle Checkpoint Silencing

2018 ◽  
Author(s):  
Spyridon T. Pachis ◽  
Yoshitaka Hiruma ◽  
Anastassis Perrakis ◽  
Geert J.P.L. Kops
Keyword(s):  
Chromosome Segregation ◽  
Mitotic Spindle ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Intramolecular Interactions ◽  
Mitotic Progression ◽  
Microtubule Attachment ◽  
Anaphase Onset ◽  
Regulatory Input ◽  
Tpr Domain

ABSTRACTFaithful chromosome segregation relies on the ability of the spindle assembly checkpoint (SAC) to delay anaphase onset until all chromosomes are attached to the mitotic spindle via their kinetochores. MPS1 kinase is recruited to unattached kinetochores to initiate SAC signaling, and is removed from kinetochores once stable microtubule attachments have been formed to allow normal mitotic progression. Here we show that a helical fragment within the kinetochore-targeting NTE module of MPS1 is required for interactions with kinetochores, and also forms intramolecular interactions with its adjacent TPR domain. Bypassing this NTE-TPR interaction results in high MPS1 levels at kinetochores due to loss of regulatory input into MPS1 localization, ineffecient MPS1 delocalization from kinetochores upon microtubule attachment, and SAC silencing defects. These results show that SAC responsiveness to attachments relies on regulated intramolecular interactions in MPS1 and highlight the sensitivity of mitosis to perturbations in the dynamics of the MSP1-NDC80-C interactions.

scholarly journals Spindle assembly checkpoint satisfaction occurs through end-on but not lateral kinetochore-microtubule interactions under tension

2017 ◽  
Author(s):  
Jonathan Kuhn ◽  
Sophie Dumont
Keyword(s):  
Real Time ◽  
Chromosome Segregation ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Microtubule Attachment ◽  
Normal Mitosis

AbstractTo ensure accurate chromosome segregation, the spindle assembly checkpoint (SAC) prevents anaphase until all kinetochores attach to the spindle. What signals the SAC monitors remains unclear. We do not know the contributions of different microtubule attachment features, or tension from biorientation, to SAC satisfaction in normal mitosis - or how these possible cues change during attachment. Here, we quantify concurrent Mad1 intensity, reporting on SAC silencing, and real-time attachment geometry, occupancy, and tension at individual mammalian kinetochores. We show that Mad1 loss from the kinetochore occurs in switch-like events with robust kinetics, and that metaphase-like tension across sister kinetochores is established just before Mad1 loss events at the first sister. We demonstrate that CenpE-mediated lateral attachment of the second sister can persistently generate this metaphase-like tension prior to biorientation, likely stabilizing sister end-on attachment, yet cannot induce Mad1 loss from that kinetochore. Instead, Mad1 loss begins after several end-on microtubules attach. Thus, end-on attachment provides geometry-specific molecular cues, or force on specific kinetochore linkages, that other attachment geometries cannot provide.SummaryThe spindle assembly checkpoint (SAC) delays anaphase until kinetochores are properly attached to the spindle. The authors demonstrate that the SAC monitors geometry-specific molecular cues, or force on specific kinetochore linkages, that “end-on” but not “lateral” attachments generating persistent tension can provide.

scholarly journals BUB-1 promotes amphitelic chromosome biorientation via multiple activities at the kinetochore

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Frances Edwards ◽  
Gilliane Maton ◽  
Nelly Gareil ◽  
Julie C Canman ◽  
Julien Dumont
Keyword(s):  
Chromosome Segregation ◽  
Spindle Assembly Checkpoint ◽  
Underlying Mechanism ◽  
Microtubule Assembly ◽  
Spindle Poles ◽  
Microtubule Attachment ◽  
Anaphase Onset ◽  
Chromatid Segregation ◽  
Associated Proteins ◽  
Chromosome Attachment

Accurate chromosome segregation relies on bioriented amphitelic attachments of chromosomes to microtubules of the mitotic spindle, in which sister chromatids are connected to opposite spindle poles. BUB-1 is a protein of the Spindle Assembly Checkpoint (SAC) that coordinates chromosome attachment with anaphase onset. BUB-1 is also required for accurate sister chromatid segregation independently of its SAC function, but the underlying mechanism remains unclear. Here we show that, in Caenorhabditis elegans embryos, BUB-1 accelerates the establishment of non-merotelic end-on kinetochore-microtubule attachments by recruiting the RZZ complex and its downstream partner dynein-dynactin at the kinetochore. In parallel, BUB-1 limits attachment maturation by the SKA complex. This activity opposes kinetochore-microtubule attachment stabilisation promoted by CLS-2CLASP-dependent kinetochore-microtubule assembly. BUB-1 is therefore a SAC component that coordinates the function of multiple downstream kinetochore-associated proteins to ensure accurate chromosome segregation.

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