Faculty Opinions recommendation of Age-dependent integrity of the meiotic spindle assembly checkpoint in females requires Aurora kinase B.

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.

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Cell-based screen for altered nuclear phenotypes reveals senescence progression in polyploid cells after Aurora kinase B inhibition

Molecular Biology of the Cell ◽

10.1091/mbc.e15-01-0003 ◽

2015 ◽

Vol 26 (17) ◽

pp. 2971-2985 ◽

Cited By ~ 26

Author(s):

Mahito Sadaie ◽

Christian Dillon ◽

Masashi Narita ◽

Andrew R. J. Young ◽

Claire J. Cairney ◽

...

Keyword(s):

Spindle Assembly Checkpoint ◽

Kinase Inhibitor ◽

Aurora Kinase ◽

Small Population ◽

Aurora Kinase B ◽

Human Diploid Fibroblasts ◽

Oncogenic Ras ◽

Chromosome Passenger Complex ◽

Progressive Accumulation

Cellular senescence is a widespread stress response and is widely considered to be an alternative cancer therapeutic goal. Unlike apoptosis, senescence is composed of a diverse set of subphenotypes, depending on which of its associated effector programs are engaged. Here we establish a simple and sensitive cell-based prosenescence screen with detailed validation assays. We characterize the screen using a focused tool compound kinase inhibitor library. We identify a series of compounds that induce different types of senescence, including a unique phenotype associated with irregularly shaped nuclei and the progressive accumulation of G1 tetraploidy in human diploid fibroblasts. Downstream analyses show that all of the compounds that induce tetraploid senescence inhibit Aurora kinase B (AURKB). AURKB is the catalytic component of the chromosome passenger complex, which is involved in correct chromosome alignment and segregation, the spindle assembly checkpoint, and cytokinesis. Although aberrant mitosis and senescence have been linked, a specific characterization of AURKB in the context of senescence is still required. This proof-of-principle study suggests that our protocol is capable of amplifying tetraploid senescence, which can be observed in only a small population of oncogenic RAS-induced senescence, and provides additional justification for AURKB as a cancer therapeutic target.

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Aurora Kinase-A Inactivates DNA Damage-Induced Apoptosis and Spindle Assembly Checkpoint Response Functions of p73

Cancer Cell ◽

10.1016/j.ccr.2011.12.025 ◽

2012 ◽

Vol 21 (2) ◽

pp. 196-211 ◽

Cited By ~ 50

Author(s):

Hiroshi Katayama ◽

Jin Wang ◽

Warapen Treekitkarnmongkol ◽

Hidehiko Kawai ◽

Kaori Sasai ◽

...

Keyword(s):

Dna Damage ◽

Spindle Assembly Checkpoint ◽

Spindle Assembly ◽

Aurora Kinase ◽

Response Functions ◽

Checkpoint Response ◽

Aurora Kinase A ◽

Induced Apoptosis ◽

Kinase A

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APCFZR1 prevents nondisjunction in mouse oocytes by controlling meiotic spindle assembly timing

Molecular Biology of the Cell ◽

10.1091/mbc.e12-05-0352 ◽

2012 ◽

Vol 23 (20) ◽

pp. 3970-3981 ◽

Cited By ~ 24

Author(s):

Janet E. Holt ◽

Simon I. R. Lane ◽

Phoebe Jennings ◽

Irene García-Higuera ◽

Sergio Moreno ◽

...

Keyword(s):

Spindle Assembly Checkpoint ◽

Spindle Assembly ◽

Mitotic Cell ◽

Meiotic Spindle ◽

Genome Integrity ◽

Mitotic Cell Cycle ◽

Anaphase Promoting Complex ◽

Mouse Oocytes ◽

M Phase ◽

Chromosome Nondisjunction

FZR1 is an anaphase-promoting complex (APC) activator best known for its role in the mitotic cell cycle at M-phase exit, in G1, and in maintaining genome integrity. Previous studies also established that it prevents meiotic resumption, equivalent to the G2/M transition. Here we report that mouse oocytes lacking FZR1 undergo passage through meiosis I that is accelerated by ∼1 h, and this is due to an earlier onset of spindle assembly checkpoint (SAC) satisfaction and APCCDC20 activity. However, loss of FZR1 did not compromise SAC functionality; instead, earlier SAC satisfaction was achieved because the bipolar meiotic spindle was assembled more quickly in the absence of FZR1. This novel regulation of spindle assembly by FZR1 led to premature bivalent attachment to microtubules and loss of kinetochore-bound MAD2. Bivalents, however, were observed to congress poorly, leading to nondisjunction rates of 25%. We conclude that in mouse oocytes FZR1 controls the timing of assembly of the bipolar spindle and in so doing the timing of SAC satisfaction and APCCDC20 activity. This study implicates FZR1 as a major regulator of prometaphase whose activity helps to prevent chromosome nondisjunction.

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BRCA1 Is Required for Meiotic Spindle Assembly and Spindle Assembly Checkpoint Activation in Mouse Oocytes1

Biology of Reproduction ◽

10.1095/biolreprod.108.069641 ◽

2008 ◽

Vol 79 (4) ◽

pp. 718-726 ◽

Cited By ~ 38

Author(s):

Bo Xiong ◽

Sen Li ◽

Jun-Shu Ai ◽

Shen Yin ◽

Ying-Chun OuYang ◽

...

Keyword(s):

Spindle Assembly Checkpoint ◽

Spindle Assembly ◽

Meiotic Spindle ◽

Checkpoint Activation

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Novel roles for BicD in pronuclear fusion and meiosis II progression via localization of the CHC/TACC/Msps complex to MII spindles

10.1101/2020.12.22.423980 ◽

2020 ◽

Author(s):

Paula Vazquez-Pianzola ◽

Dirk Beuchle ◽

Gabriela Saro ◽

Greco Hernández ◽

Giovanna Maldonado ◽

...

Keyword(s):

Heavy Chain ◽

Spindle Assembly Checkpoint ◽

Coiled Coil ◽

Spindle Assembly ◽

Meiotic Spindle ◽

C Elegans ◽

Spindle Apparatus ◽

Spindle Microtubules ◽

Mitosis And Meiosis ◽

Overexpressed Gene

ABSTRACTVertebrate Clathrin heavy chain (Chc) plays a moonlighting function during mitosis. Chc forms a complex with TACC3 (Transforming Acidic Coiled Coil 3) and ch-TOG (colonic hepatic tumor overexpressed gene) at the spindle microtubules, forming inter microtubule bridges that stabilize the K-fibers. Since Drosophila Chc is a cargo of the dynein adaptor Bicaudal-D (BicD), we investigated whether BicD regulates Clathrin function at the spindle. We found that BicD localizes, like Chc, to centrosomes and spindles during mitosis and meiosis II, and that Chc interacts with Drosophila TACC (D-TACC). Using deGradFP to reduce the activity of BicD in mature eggs and very young embryos, we uncovered a novel function of BicD in meiosis II. The affected meiosis II products underwent abnormal rounds of additional replications and failed to carry out pronuclear fusion. Pointing to a mechanism, we found that the localization of Clathrin/D-TACC/Minispindles (Msps, homolog of ch-TOG) to the meiosis II spindles was impaired upon BicD knockdown. Furthermore, the meiotic products showed abnormal staining for PH3 and reduced recruitment of spindle assembly checkpoint (SAC) components. Altogether, our results support the notion that BicD performs a key activity in assembling the meiotic spindle apparatus. This function of BicD seems conserved in evolution because C. elegans embryos with reduced activities of these genes developed comparable phenotypes.

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EMB-30: An APC4 Homologue Required for Metaphase-to-Anaphase Transitions during Meiosis and Mitosis in Caenorhabditis elegans

Molecular Biology of the Cell ◽

10.1091/mbc.11.4.1401 ◽

2000 ◽

Vol 11 (4) ◽

pp. 1401-1419 ◽

Cited By ~ 72

Author(s):

Tokiko Furuta ◽

Simon Tuck ◽

Jay Kirchner ◽

Bryan Koch ◽

Roy Auty ◽

...

Keyword(s):

Positional Cloning ◽

Spindle Assembly Checkpoint ◽

Spindle Assembly ◽

Class I ◽

Meiotic Spindle ◽

Anaphase Promoting Complex ◽

Anaphase Onset ◽

Polar Bodies ◽

M Phase ◽

Set Up

Here we show that emb-30 is required for metaphase-to-anaphase transitions during meiosis and mitosis inCaenorhabditis elegans. Germline-specificemb-30 mutant alleles block the meiotic divisions. Mutant oocytes, fertilized by wild-type sperm, set up a meiotic spindle but do not progress to anaphase I. As a result, polar bodies are not produced, pronuclei fail to form, and cytokinesis does not occur. Severe-reduction-of-function emb-30 alleles (class I alleles) result in zygotic sterility and lead to germline and somatic defects that are consistent with an essential role in promoting the metaphase-to-anaphase transition during mitosis. Analysis of the vulval cell lineages in these emb-30(class I) mutant animals suggests that mitosis is lengthened and eventually arrested when maternally contributed emb-30 becomes limiting. By further reducing maternal emb-30 function contributed to class I mutant animals, we show that emb-30 is required for the metaphase-to-anaphase transition in many, if not all, cells. Metaphase arrest in emb-30 mutants is not due to activation of the spindle assembly checkpoint but rather reflects an essential emb-30 requirement for M-phase progression. A reduction in emb-30 activity can suppress the lethality and sterility caused by a null mutation in mdf-1, a component of the spindle assembly checkpoint machinery. This result suggests that delaying anaphase onset can bypass the spindle checkpoint requirement for normal development. Positional cloning established thatemb-30 encodes the likely C. elegansorthologue of APC4/Lid1, a component of the anaphase-promoting complex/cyclosome, required for the metaphase-to-anaphase transition. Thus, the anaphase-promoting complex/cyclosome is likely to be required for all metaphase-to-anaphase transitions in a multicellular organism.

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CDC6 regulates both G2/M transition and metaphase-to-anaphase transition during the first meiosis of mouse oocytes

10.1101/587238 ◽

2019 ◽

Author(s):

Zi-Yun Yi ◽

Tie-Gang Meng ◽

Xue-Shan Ma ◽

Jian Li ◽

Chun-Hui Zhang ◽

...

Keyword(s):

Spindle Assembly Checkpoint ◽

Spindle Assembly ◽

Time Lapse ◽

Cyclin B1 ◽

Meiotic Spindle ◽

G2 Arrest ◽

Mouse Oocytes ◽

Summary Statement ◽

Initiation Of Dna Replication ◽

Oocyte Meiotic Maturation

AbstractCell division cycle protein CDC6 is essential for the initiation of DNA replication. CDC6 was recently shown to inhibit the microtubule-organizing activity of the centrosome. Here, we show that CDC6 is localized to the spindle from Pro-MI to MII stages of oocytes, and it plays important roles at two critical steps of oocyte meiotic maturation. CDC6 depletion facilitated the G2/M transition (GV breakdown, GVBD) through regulation of Cdh1 and cyclin B1 expression and CDK1 phosphorylation in a GVBD-inhibiting culture system containing milrinone. Furthermore, GVBD was significantly decreased after knockdown of cyclin B1 in CDC6-depleted oocytes, indicating that the effect of CDC6 loss on GVBD stimulation was mediated, at least in part, by raising cyclin B1. Knockdown of CDC6 also caused abnormal localization of γ-tubulin, resulting in defective spindles, misaligned chromosomes, cyclin B1 accumulation and spindle assembly checkpoint (SAC) activation, leading to significant Pro-MI/MI arrest and PB1 extrusion failure. These phenotypes were also confirmed by time-lapse live cell imaging analysis. The results indicate that CDC6 is indispensable for maintaining G2 arrest of meiosis and functions in G2/M checkpoint regulation in mouse oocytes. Moreover, CDC6 is also a key player regulating meiotic spindle assembly and metaphase-to-anaphase transition in meiotic oocytes.Summary statementWe show that CDC6 is indispensable for maintaining G2 arrest of mouse oocytes. Moreover, CDC6 is also a key player regulating meiotic spindle assembly and metaphase-to-anaphase transition in meiotic oocytes.

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