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Live Cell Imaging to Assess the Dynamics of Metaphase Timing and Cell Fate Following Mitotic Spindle Perturbations
Published on: September 20, 2019
An ATM and ATR dependent pathway targeting centrosome dependent spindle assembly
Nicola Brown1, Vincenzo Costanzo
1Genome Stability Unit, London Research Institute, Clare Hall Laboratories, South Mimms, Herts, UK.
Cell Cycle (Georgetown, Tex.)
|June 9, 2009
Summary
A DNA damage checkpoint involving ATM and ATR proteins regulates spindle assembly during mitosis when chromosome breaks occur. This pathway, dependent on CEP63 protein phosphorylation, is crucial for maintaining genome stability.
Area of Science:
- Cell Biology
- Molecular Biology
- Genetics
Background:
- The DNA damage checkpoint halts DNA replication and mitosis under genotoxic stress.
- Cellular responses to DNA double-strand breaks (DSBs) during mitosis remain incompletely understood.
Purpose of the Study:
- To investigate how cells respond to DNA damage, specifically DSBs, during mitosis.
- To identify molecular mechanisms linking DNA damage checkpoints to spindle assembly in mitosis.
Main Methods:
- Utilized Xenopus laevis egg extract as a model system.
- Investigated the roles of ATM and ATR kinases and the novel centrosomal protein CEP63.
- Examined spindle assembly in Xenopus and chicken DT40 cells.
Main Results:
- Discovered an ATM and ATR-dependent checkpoint targeting centrosome-dependent spindle assembly in the presence of chromosome breaks.
- CEP63 phosphorylation by ATM/ATR causes its delocalization from centrosomes, impairing spindle assembly.
- CEP63 is essential for proper spindle assembly in both Xenopus and DT40 cells.
Conclusions:
- A novel DNA damage checkpoint pathway involving ATM, ATR, and CEP63 regulates spindle assembly during mitosis.
- This pathway is critical for maintaining genome stability by controlling centrosome function in response to DNA breaks.
Related Concept Videos
02:50Spindle Assembly
Spindle assembly occurs through three, often coexisting, pathways – the centrosome-mediated pathway, the chromatin-mediated pathway, and the microtubule-mediated pathway – collectively contributing to form a robust spindle apparatus.
In most cells, centrosomes are the primary microtubule nucleation centers. In the centrosome-mediated pathway, the G2-prophase transition triggers centrosome maturation and increased microtubule nucleation. Progressive nucleation results in a microtubule array...
In most cells, centrosomes are the primary microtubule nucleation centers. In the centrosome-mediated pathway, the G2-prophase transition triggers centrosome maturation and increased microtubule nucleation. Progressive nucleation results in a microtubule array...
02:19The Spindle Assembly Checkpoint
The spindle assembly checkpoint is a molecular surveillance mechanism ensuring the fidelity of chromosome segregation during anaphase. The checkpoint monitors the completion of all the prerequisite steps before chromosome segregation to determine whether the segregation process should proceed or be delayed.
Many proteins function together to control the spindle assembly checkpoint. Mutations affecting these proteins may allow cells to proceed into anaphase prematurely, resulting in the...
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02:19The Spindle Assembly Checkpoint
The spindle assembly checkpoint is a molecular surveillance mechanism ensuring the fidelity of chromosome segregation during anaphase. The checkpoint monitors the completion of all the prerequisite steps before chromosome segregation to determine whether the segregation process should proceed or be delayed.
Many proteins function together to control the spindle assembly checkpoint. Mutations affecting these proteins may allow cells to proceed into anaphase prematurely, resulting in the...
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02:57Attachment of Sister Chromatids
As cells progress into mitosis, the nuclear envelope breaks down, and the condensed chromosomes are exposed to the array of bipolar microtubules of the mitotic spindle. The kinetochore, a large, disc-shaped protein complex, is present at the centromere region of the sister chromatids and acts as a binding site for the microtubules. Usually, the plus-end of a single microtubule is embedded within the kinetochore. However, some kinetochores first establish lateral contact with the side-wall of a...
01:39Anaphase A and B
Microtubules form through the end-to-end polymerization of tubulin heterodimers. Kinetochore microtubules originate from the spindle poles, and their plus-ends connect with the kinetochores on sister-chromatids. Ndc80 protein complexes, present on the kinetochore, form low-affinity links with the plus end of these kinetochore microtubules.
Plus-end depolymerization releases tubulin heterodimers from the terminal region of the microtubule. As tubulin subunits are lost, the Ndc80 complexes detach...
Plus-end depolymerization releases tubulin heterodimers from the terminal region of the microtubule. As tubulin subunits are lost, the Ndc80 complexes detach...
02:27The Mitotic Spindle
The mitotic spindle—or spindle apparatus—is a eukaryotic, cytoskeletal structure made up of long protein fibers called microtubules. Formed during cell division, the spindle separates sister chromatids and moves them to opposite ends of a parental cell, where the now individual chromosomes are distributed to two daughter cell nuclei.
The bipolar configuration of the mitotic spindle facilitates chromosomal segregation, preparing the cell for division. One mechanism that ensures bipolar mitotic...
The bipolar configuration of the mitotic spindle facilitates chromosomal segregation, preparing the cell for division. One mechanism that ensures bipolar mitotic...