scholarly journals Cyclin B1-Cdk1 binding to MAD1 links nuclear pore disassembly to chromosomal stability

2019 ◽  
Author(s):  
Mark Jackman ◽  
Chiara Marcozzi ◽  
Mercedes Pardo ◽  
Lu Yu ◽  
Adam L. Tyson ◽  
...  
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Cyclin B1 ◽  
Nuclear Pore ◽  
Major Question ◽  
Nuclear Envelope Breakdown ◽  
Kinetochore Assembly ◽  
Regulatory Machinery ◽  
Multiple Protein ◽  
Spindle Assembly Checkpoint Protein

AbstractHow the cell completely reorganises its architecture when it divides is a problem that has fascinated researchers for almost 150 years. We now know that the core regulatory machinery is highly conserved in eukaryotes but how these multiple protein kinases, protein phosphatases, and ubiquitin ligases are coordinated to remodel the cell in a matter of minutes remains a major question. Cyclin B-CDK is the primary kinase that drives mitotic remodelling and here we show that it is targeted to the nuclear pore complex (NPC) by binding an acidic face of the spindle assembly checkpoint protein, MAD1. This localised Cyclin B1-CDK1 activity coordinates NPC disassembly with kinetochore assembly: it is needed for the proper release of MAD1 from the embrace of TPR at the nuclear pore, which enables MAD1 to be recruited to kinetochores before nuclear envelope breakdown, thereby strengthening the spindle assembly checkpoint to maintain genomic stability.

scholarly journals Cyclin B1-Cdk1 facilitates MAD1 release from the nuclear pore to ensure a robust spindle checkpoint

2020 ◽  
Vol 219 (6) ◽  
Author(s):  
Mark Jackman ◽  
Chiara Marcozzi ◽  
Martina Barbiero ◽  
Mercedes Pardo ◽  
Lu Yu ◽  
...  
Keyword(s):  
Genomic Stability ◽  
Cyclin B1 ◽  
Nuclear Pore ◽  
Major Question ◽  
Checkpoint Protein ◽  
Nuclear Envelope Breakdown ◽  
The Core ◽  
Kinetochore Assembly ◽  
Regulatory Machinery ◽  
Multiple Protein

How the cell rapidly and completely reorganizes its architecture when it divides is a problem that has fascinated researchers for almost 150 yr. We now know that the core regulatory machinery is highly conserved in eukaryotes, but how these multiple protein kinases, protein phosphatases, and ubiquitin ligases are coordinated in space and time to remodel the cell in a matter of minutes remains a major question. Cyclin B1-Cdk is the primary kinase that drives mitotic remodeling; here we show that it is targeted to the nuclear pore complex (NPC) by binding an acidic face of the kinetochore checkpoint protein, MAD1, where it coordinates NPC disassembly with kinetochore assembly. Localized cyclin B1-Cdk1 is needed for the proper release of MAD1 from the embrace of TPR at the nuclear pore so that it can be recruited to kinetochores before nuclear envelope breakdown to maintain genomic stability.

Spindle Assembly Checkpoint Protein Dynamics and Roles in Plant Cell Division

2011 ◽  
pp. 142-153
Author(s):  
Marie-Cécile Caillaud ◽  
Laetitia Paganelli ◽  
Philippe Lecomte ◽  
Laurent Deslandes ◽  
Michaël Quentin ◽  
...  
Keyword(s):  
Cell Division ◽  
Protein Dynamics ◽  
Plant Cell ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Checkpoint Protein ◽  
Plant Cell Division ◽  
Spindle Assembly Checkpoint Protein

scholarly journals Orchestration of the spindle assembly checkpoint by CDK1‐cyclin B1

FEBS Letters ◽  
2019 ◽  
Vol 593 (20) ◽  
pp. 2889-2907 ◽  
Author(s):  
Daniel Hayward ◽  
Tatiana Alfonso‐Pérez ◽  
Ulrike Gruneberg
Keyword(s):  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Cyclin B1

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 Spindle assembly checkpoint robustness requires Tpr-mediated regulation of Mad1/Mad2 proteostasis

2013 ◽  
Vol 203 (6) ◽  
pp. 883-893 ◽  
Author(s):  
Nina Schweizer ◽  
Cristina Ferrás ◽  
David M. Kern ◽  
Elsa Logarinho ◽  
Iain M. Cheeseman ◽  
...  
Keyword(s):  
Nuclear Pore Complex ◽  
Half Life ◽  
Spindle Assembly Checkpoint ◽  
Spindle Assembly ◽  
Limiting Factor ◽  
Nuclear Pore ◽  
Independent Manner ◽  
Unknown Mechanism ◽  
Rate Limiting

Tpr is a conserved nuclear pore complex (NPC) protein implicated in the spindle assembly checkpoint (SAC) by an unknown mechanism. Here, we show that Tpr is required for normal SAC response by stabilizing Mad1 and Mad2 before mitosis. Tpr coimmunoprecipitated with Mad1 and Mad2 (hereafter designated as Tpr/Mad1/Mad2 or TM2 complex) during interphase and mitosis, and is required for Mad1–c-Mad2 recruitment to NPCs. Interestingly, Tpr was normally undetectable at kinetochores and dispensable for Mad1, but not for Mad2, kinetochore localization, which suggests that SAC robustness depends on Mad2 levels at kinetochores. Protein half-life measurements demonstrate that Tpr stabilizes Mad1 and Mad2, ensuring normal Mad1–c-Mad2 production in an mRNA- and kinetochore-independent manner. Overexpression of GFP-Mad2 restored normal SAC response and Mad2 kinetochore levels in Tpr-depleted cells. Mechanistically, we provide evidence that Tpr might spatially regulate SAC proteostasis through the SUMO-isopeptidases SENP1 and SENP2 at NPCs. Thus, Tpr is a kinetochore-independent, rate-limiting factor required to mount and sustain a robust SAC response.

scholarly journals DNA Damage during the Spindle-Assembly Checkpoint Degrades CDC25A, Inhibits Cyclin–CDC2 Complexes, and Reverses Cells to Interphase

2003 ◽  
Vol 14 (10) ◽  
pp. 3989-4002 ◽  
Author(s):  
Jeremy P.H. Chow ◽  
Wai Yi Siu ◽  
Tsz Kan Fung ◽  
Wan Mui Chan ◽  
Anita Lau ◽  
...  
Keyword(s):  
Dna Damage ◽  
Spindle Assembly Checkpoint ◽  
Histone H3 ◽  
Ectopic Expression ◽  
Spindle Assembly ◽  
Cyclin B1 ◽  
Chemotherapeutic Agents ◽  
Cell Cycle Checkpoints ◽  
Dependent Manner ◽  
Mitotic Block

Cell cycle checkpoints that monitor DNA damage and spindle assembly are essential for the maintenance of genetic integrity, and drugs that target these checkpoints are important chemotherapeutic agents. We have examined how cells respond to DNA damage while the spindle-assembly checkpoint is activated. Single cell electrophoresis and phosphorylation of histone H2AX indicated that several chemotherapeutic agents could induce DNA damage during mitotic block. DNA damage during mitotic block triggered CDC2 inactivation, histone H3 dephosphorylation, and chromosome decondensation. Cells did not progress into G1 but seemed to retract to a G2-like state containing 4N DNA content, with stabilized cyclin A and cyclin B1 binding to Thr14/Tyr15-phosphorylated CDC2. The loss of mitotic cells was not due to cell death because there was no discernible effect on caspase-3 activation, DNA fragmentation, or viability. Extensive DNA damage during mitotic block inactivated cyclin B1-CDC2 and prevented G1 entry when the block was removed. The mitotic DNA damage responses were independent of p53 and pRb, but they were dependent on ATM. CDC25A that accumulated during mitosis was rapidly destroyed after DNA damage in an ATM-dependent manner. Ectopic expression of CDC25A or nonphosphorylatable CDC2 effectively inhibited the dephosphorylation of histone H3 after DNA damage. Hence, although spindle disruption and DNA damage provide conflicting signals to regulate CDC2, the negative regulation by the DNA damage checkpoint could overcome the positive regulation by the spindle-assembly checkpoint.

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