scholarly journals Spindle assembly checkpoint proteins regulate and monitor meiotic synapsis in C. elegans

2015 ◽  
Vol 211 (2) ◽  
pp. 233-242 ◽  
Author(s):  
Tisha Bohr ◽  
Christian R. Nelson ◽  
Erin Klee ◽  
Needhi Bhalla
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Meiotic Chromosome ◽  
Spindle Assembly ◽  
Anaphase Promoting Complex ◽  
Checkpoint Response ◽  
Checkpoint Proteins ◽  
Cis Acting ◽  
C Elegans ◽  
Meiotic Synapsis ◽  
The Stability

Homologue synapsis is required for meiotic chromosome segregation, but how synapsis is initiated between chromosomes is poorly understood. In Caenorhabditis elegans, synapsis and a checkpoint that monitors synapsis depend on pairing centers (PCs), cis-acting loci that interact with nuclear envelope proteins, such as SUN-1, to access cytoplasmic microtubules. Here, we report that spindle assembly checkpoint (SAC) components MAD-1, MAD-2, and BUB-3 are required to negatively regulate synapsis and promote the synapsis checkpoint response. Both of these roles are independent of a conserved component of the anaphase-promoting complex, indicating a unique role for these proteins in meiotic prophase. MAD-1 and MAD-2 localize to the periphery of meiotic nuclei and interact with SUN-1, suggesting a role at PCs. Consistent with this idea, MAD-1 and BUB-3 require full PC function to inhibit synapsis. We propose that SAC proteins monitor the stability of pairing, or tension, between homologues to regulate synapsis and elicit a checkpoint response.

scholarly journals Synaptonemal complex components are required for meiotic checkpoint function in C. elegans

2016 ◽  
Author(s):  
Tisha Bohr ◽  
Guinevere Ashley ◽  
Evan Eggleston ◽  
Kyra Firestone ◽  
Needhi Bhalla
Keyword(s):  
Synaptonemal Complex ◽  
Chromosome Segregation ◽  
Meiotic Chromosome ◽  
Checkpoint Response ◽  
Homologous Chromosomes ◽  
C Elegans ◽  
Homolog Pairing ◽  
The Stability ◽  
Complex Components

AbstractSynapsis involves the assembly of a proteinaceous structure, the synaptonemal complex (SC), between paired homologous chromosomes and is essential for proper meiotic chromosome segregation. In C. elegans, the synapsis checkpoint selectively removes nuclei with unsynapsed chromosomes by inducing apoptosis. This checkpoint depends on Pairing Centers (PCs), cis-acting sites that promote pairing and synapsis. We have hypothesized that the stability of homolog pairing at PCs is monitored by this checkpoint. Here, we report that SC components SYP-3, HTP-3, HIM-3 and HTP-1 are required for a functional synapsis checkpoint. Mutation of these components does not abolish PC function, demonstrating they are bonafide checkpoint components. Further, we identify mutant backgrounds in which the instability of homolog pairing at PCs does not correlate with the synapsis checkpoint response. Altogether, these data suggest that, in addition to homolog pairing, SC assembly may be monitored by the synapsis checkpoint.

scholarly journals Spindle assembly checkpoint: the third decade

2011 ◽  
Vol 366 (1584) ◽  
pp. 3595-3604 ◽  
Author(s):  
Andrea Musacchio
Keyword(s):  
Cell Cycle Progression ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Mitotic Checkpoint ◽  
Anaphase Promoting Complex ◽  
Checkpoint Control ◽  
Checkpoint Response ◽  
The Third ◽  
Binding Interface ◽  
Mitotic Checkpoint Complex

The spindle assembly checkpoint controls cell cycle progression during mitosis, synchronizing it with the attachment of chromosomes to spindle microtubules. After the discovery of the mitotic arrest deficient ( MAD ) and budding uninhibited by benzymidazole ( BUB ) genes as crucial checkpoint components in 1991, the second decade of checkpoint studies (2001–2010) witnessed crucial advances in the elucidation of the mechanism through which the checkpoint effector, the mitotic checkpoint complex, targets the anaphase-promoting complex (APC/C) to prevent progression into anaphase. Concomitantly, the discovery that the Ndc80 complex and other components of the microtubule-binding interface of kinetochores are essential for the checkpoint response finally asserted that kinetochores are crucial for the checkpoint response. Nevertheless, the relationship between kinetochores and checkpoint control remains poorly understood. Crucial advances in this area in the third decade of checkpoint studies (2011–2020) are likely to be brought about by the characterization of the mechanism of kinetochore recruitment, activation and inactivation of checkpoint proteins, which remains elusive for the majority of checkpoint components. Here, we take a molecular view on the main challenges hampering this task.

scholarly journals Retracted: Three BUB1 and BUBR1/MAD3-related spindle assembly checkpoint proteins are required for accurate mitosis in Arabidopsis

2014 ◽  
Vol 205 (1) ◽  
pp. 202-215 ◽  
Author(s):  
Laetitia Paganelli ◽  
Marie-Cécile Caillaud ◽  
Michaël Quentin ◽  
Isabelle Damiani ◽  
Benjamin Govetto ◽  
...  
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Checkpoint Proteins

scholarly journals Disruption of Astral Microtubule Contact with the Cell Cortex Activates a Bub1, Bub3, and Mad3-dependent Checkpoint in Fission Yeast

2004 ◽  
Vol 15 (7) ◽  
pp. 3345-3356 ◽  
Author(s):  
Sylvie Tournier ◽  
Yannick Gachet ◽  
Vicky Buck ◽  
Jeremy S. Hyams ◽  
Jonathan B.A. Millar
Keyword(s):  
Actin Cytoskeleton ◽  
Fission Yeast ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Yeast Cells ◽  
Cell Cortex ◽  
Checkpoint Proteins ◽  
Sister Chromatids ◽  
Astral Microtubule ◽  
Spindle Rotation

In animal and yeast cells, the mitotic spindle is aligned perpendicularly to the axis of cell division. This ensures that sister chromatids are separated to opposite sides of the cytokinetic actomyosin ring. In fission yeast, spindle rotation is dependent upon the interaction of astral microtubules with the cortical actin cytoskeleton. In this article, we show that addition of Latrunculin A, which prevents spindle rotation, delays the separation of sister chromatids and anaphase promoting complex-mediated destruction of spindle-associated Securin and Cyclin B. Moreover, we find that whereas sister kinetochore pairs normally congress to the spindle midzone before anaphase onset, this congression is disrupted when astral microtubule contact with the actin cytoskeleton is disturbed. By analyzing the timing of kinetochore separation, we find that this anaphase delay requires the Bub3, Mad3, and Bub1 but not the Mad1 or Mad2 spindle assembly checkpoint proteins. In agreement with this, we find that Bub1 remains associated with kinetochores when spindles are mispositioned. These data indicate that, in fission yeast, astral microtubule contact with the medial cell cortex is monitored by a subset of spindle assembly checkpoint proteins. We propose that this checkpoint ensures spindles are properly oriented before anaphase takes place.

scholarly journals Uncoupling Anaphase-Promoting Complex/Cyclosome Activity from Spindle Assembly Checkpoint Control by Deregulating Polo-Like Kinase 1

2005 ◽  
Vol 25 (5) ◽  
pp. 2031-2044 ◽  
Author(s):  
Barbara C. M. van de Weerdt ◽  
Marcel A. T. M. van Vugt ◽  
Catherine Lindon ◽  
Jos J. W. Kauw ◽  
Marieke J. Rozendaal ◽  
...  
Keyword(s):  
Double Mutant ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Mitotic Catastrophe ◽  
Anaphase Promoting Complex ◽  
Checkpoint Control ◽  
Mitotic Progression ◽  
Specific Antibodies ◽  
Mitotic Entry

ABSTRACT Polo-like kinase 1 (Plk1) plays a role in numerous events in mitosis, but how the multiple functions of Plk1 are separated is poorly understood. We studied regulation of Plk1 through two putative phosphorylation residues, Ser-137 and Thr-210. Using phospho-specific antibodies, we found that Thr-210 phosphorylation precedes Ser-137 phosphorylation in vivo, the latter occurring specifically in late mitosis. We show that expression of two activating mutants of these residues, S137D and T210D, results in distinct mitotic phenotypes. Whereas expression of both phospho-mimicking mutants as well as of the double mutant leads to accelerated mitotic entry, further progression through mitosis is dramatically different: the T210D mutant causes a spindle assembly checkpoint-dependent delay, whereas the expression of the S137D mutant or the double mutant results in untimely activation of the anaphase-promoting complex/cyclosome (APC/C) and frequent mitotic catastrophe. Using nonphosphorylatable Plk1-S137A and Plk1-T210A mutants, we show that both sites contribute to proper mitotic progression. Based on these observations, we propose that Plk1 function is altered at different stages of mitosis through consecutive posttranslational events, e.g., at Ser-137 and Thr-210. Furthermore, our data show that uncontrolled Plk1 activation can uncouple APC/C activity from spindle assembly checkpoint control.

scholarly journals The HECT E3 ligase Smurf2 is required for Mad2-dependent spindle assembly checkpoint

2008 ◽  
Vol 183 (2) ◽  
pp. 267-277 ◽  
Author(s):  
Evan C. Osmundson ◽  
Dipankar Ray ◽  
Finola E. Moore ◽  
Qingshen Gao ◽  
Gerald H. Thomsen ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Spindle Assembly Checkpoint ◽  
Spindle Checkpoint ◽  
E3 Ligase ◽  
Spindle Assembly ◽  
Cyclin B ◽  
Carboxyl Terminus ◽  
Anaphase Promoting Complex ◽  
Mitotic Spindles ◽  
Anaphase Onset

Activation of the anaphase-promoting complex/cyclosome (APC/C) by Cdc20 is critical for the metaphase–anaphase transition. APC/C-Cdc20 is required for polyubiquitination and degradation of securin and cyclin B at anaphase onset. The spindle assembly checkpoint delays APC/C-Cdc20 activation until all kinetochores attach to mitotic spindles. In this study, we demonstrate that a HECT (homologous to the E6-AP carboxyl terminus) ubiquitin ligase, Smurf2, is required for the spindle checkpoint. Smurf2 localizes to the centrosome, mitotic midbody, and centromeres. Smurf2 depletion or the expression of a catalytically inactive Smurf2 results in misaligned and lagging chromosomes, premature anaphase onset, and defective cytokinesis. Smurf2 inactivation prevents nocodazole-treated cells from accumulating cyclin B and securin and prometaphase arrest. The silencing of Cdc20 in Smurf2-depleted cells restores mitotic accumulation of cyclin B and securin. Smurf2 depletion results in enhanced polyubiquitination and degradation of Mad2, a critical checkpoint effector. Mad2 is mislocalized in Smurf2-depleted cells, suggesting that Smurf2 regulates the localization and stability of Mad2. These data indicate that Smurf2 is a novel mitotic regulator.

scholarly journals Spindle checkpoint proteins Mad1 and Mad2 are required for cytostatic factor–mediated metaphase arrest

2003 ◽  
Vol 163 (6) ◽  
pp. 1231-1242 ◽  
Author(s):  
Brian J. Tunquist ◽  
Patrick A. Eyers ◽  
Lin G. Chen ◽  
Andrea L. Lewellyn ◽  
James L. Maller
Keyword(s):  
Cell Cycle ◽  
Spindle Assembly Checkpoint ◽  
Spindle Checkpoint ◽  
Anaphase Promoting Complex ◽  
Metaphase Arrest ◽  
Checkpoint Proteins ◽  
Cycle Arrest ◽  
Egg Extracts ◽  
Cytostatic Factor ◽  
Sustained Inhibition

In cells containing disrupted spindles, the spindle assembly checkpoint arrests the cell cycle in metaphase. The budding uninhibited by benzimidazole (Bub) 1, mitotic arrest-deficient (Mad) 1, and Mad2 proteins promote this checkpoint through sustained inhibition of the anaphase-promoting complex/cyclosome. Vertebrate oocytes undergoing meiotic maturation arrest in metaphase of meiosis II due to a cytoplasmic activity termed cytostatic factor (CSF), which appears not to be regulated by spindle dynamics. Here, we show that microinjection of Mad1 or Mad2 protein into early Xenopus laevis embryos causes metaphase arrest like that caused by Mos. Microinjection of antibodies to either Mad1 or Mad2 into maturing oocytes blocks the establishment of CSF arrest in meiosis II, and immunodepletion of either protein blocked the establishment of CSF arrest by Mos in egg extracts. A Mad2 mutant unable to oligomerize (Mad2 R133A) did not cause cell cycle arrest in blastomeres or in egg extracts. Once CSF arrest has been established, maintenance of metaphase arrest requires Mad1, but not Mad2 or Bub1. These results suggest a model in which CSF arrest by Mos is mediated by the Mad1 and Mad2 proteins in a manner distinct from the spindle checkpoint.

scholarly journals Regulated Separation of Sister Centromeres depends on the Spindle Assembly Checkpoint but not on the Anaphase Promoting Complex/Cyclosome

Cell Cycle ◽  
2005 ◽  
Vol 4 (11) ◽  
pp. 1561-1575 ◽  
Author(s):  
Juan F. Gimenez-Abian ◽  
Laura A. Díaz-Martínez ◽  
Karin G. Wirth ◽  
Catherine A. Andrews ◽  
Gonzalo Giménez-Martín ◽  
...  
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Anaphase Promoting Complex

scholarly journals The Spindle Assembly Checkpoint Regulates the Phosphorylation State of a Subset of DNA Checkpoint Proteins in Saccharomyces cerevisiae

2006 ◽  
Vol 26 (24) ◽  
pp. 9149-9161 ◽  
Author(s):  
Céline Clémenson ◽  
Marie-Claude Marsolier-Kergoat
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Dna Damage Response ◽  
Spindle Assembly Checkpoint ◽  
Spindle Checkpoint ◽  
Spindle Assembly ◽  
Dna Lesions ◽  
Checkpoint Proteins ◽  
Cell Responses ◽  
Spindle Assembly Checkpoints ◽  
Damage Response

ABSTRACT The DNA and the spindle assembly checkpoints play key roles in maintaining genomic integrity by coordinating cell responses to DNA lesions and spindle dysfunctions, respectively. These two surveillance pathways seem to operate mostly independently of one another, and little is known about their potential physiological connections. Here, we show that in Saccharomyces cerevisiae, the activation of the spindle assembly checkpoint triggers phosphorylation changes in two components of the DNA checkpoint, Rad53 and Rad9. These modifications are independent of the other DNA checkpoint proteins and are abolished in spindle checkpoint-defective mutants, hinting at specific functions for Rad53 and Rad9 in the spindle damage response. Moreover, we found that after UV irradiation, Rad9 phosphorylation is altered and Rad53 inactivation is accelerated when the spindle checkpoint is activated, which suggests the implication of the spindle checkpoint in the regulation of the DNA damage response.

scholarly journals Spindle Assembly Checkpoint Protein Cdc20 Transcriptionally Activates Expression of Ubiquitin Carrier Protein UbcH10

2011 ◽  
Vol 286 (18) ◽  
pp. 15666-15677 ◽  
Author(s):  
Somsubhra Nath ◽  
Taraswi Banerjee ◽  
Debrup Sen ◽  
Tania Das ◽  
Susanta Roychoudhury
Keyword(s):  
Chromosomal Instability ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Regulatory Function ◽  
Physical Interaction ◽  
Anaphase Promoting Complex ◽  
Transcriptional Regulatory ◽  
Subsequent Degradation ◽  
Ubiquitin Conjugating Enzyme ◽  
Wd40 Domain

The spindle assembly checkpoint (SAC) ensures accurate segregation of chromosomes by monitoring kinetochore attachment of spindles during mitosis. Proper progression of mitosis depends on orderly ubiquitination and subsequent degradation of various mitotic inhibitors. At the molecular level, upon removal of SAC, Cdc20 activates E3 ubiquitin ligase anaphase-promoting complex/cyclosome that, along with E2 ubiquitin-conjugating enzyme UbcH10, executes this function. Both Cdc20 and UbcH10 are overexpressed in many cancer types and are associated with defective SAC function leading to chromosomal instability. The precise mechanism of correlated overexpression of these two proteins remains elusive. We show that Cdc20 transcriptionally up-regulates UbcH10 expression. The WD40 domain of Cdc20 is required for this activity. Physical interaction between Cdc20 and anaphase-promoting complex/cyclosome-CBP/p300 complex and its subsequent recruitment to the UBCH10 promoter are involved in this transactivation process. This transcriptional regulatory function of Cdc20 was observed to be cell cycle-specific. We hypothesize that this co-regulated overexpression of both proteins contributes to chromosomal instability.

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