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Centrosome Loss Requires Spindle Assembly Checkpoint-Dependent Mitotic Delay for Successful Cell Division


Core Concepts
Centrosomes provide a "timely two-ness" to mitotic spindle organization that allows cell division to occur without a spindle assembly checkpoint (SAC)-dependent mitotic delay.
Abstract
The content examines the role of the spindle assembly checkpoint (SAC) in regulating mitosis in the absence of centrosomes. Key findings: Mitotic elongation in acentrosomal cells is dependent on MPS1 kinase activity, a key SAC component. Inhibition of MPS1 leads to premature mitotic exit and division failure in acentrosomal cells. The mitotic delay mediated by the SAC is necessary for successful cell division in acentrosomal cells. Prolonging mitosis through APC/C inhibition can rescue the division failure caused by MPS1 inhibition in acentrosomal cells. Polyploidy alone is not sufficient to cause the division failure phenotype observed with MPS1 inhibition in acentrosomal cells. Centrosomes facilitate the rapid establishment of bipolar spindle organization early in mitosis. This "timely two-ness" provided by centrosomes allows cell division to occur without the need for a SAC-dependent mitotic delay. Preventing centrosome separation, even in cells with centrosomes, is sufficient to make cell division reliant on a SAC-dependent mitotic delay, similar to acentrosomal cells. In summary, the content demonstrates that centrosomes play a key role in coordinating the temporal organization of mitosis, allowing cell division to proceed efficiently even in the absence of a SAC-mediated delay.
Stats
"Acentriolar RPE-1 cells were generated in TP53-/- background, since RPE-1 cells with intact p53 pathways undergo G1 arrest in absence of centrioles." "RPE-1 TP53-/- and U2OS cells treated with centrinone showed significant increases in acentrosomal cells as compared to DMSO controls, as did TP53-/-; SASS6-/- cells in comparison to TP53-/-cells as measured by number of γ-tubulin and centrin-3 co-positive puncta, which respectively mark PCM and centrioles." "The time from nuclear envelope breakdown (NEBD) through anaphase onset was elongated in acentrosomal cells, while the duration of anaphase through cytokinesis was not significantly different compared to their appropriate controls." "Both control and acentriolar cells treated with CFI-402257 showed reduced mitotic durations." "The majority of control cells treated with CFI-402257 underwent bipolar mitoses, the majority of acentriolar cells treated with CFI-402257 rounded up and spread back out, producing a single mononucleate daughter cell." "Acentrosomal cells treated with both proTAME and CFI-402257 eventually went on to divide, after the prolonged mitotic arrest." "Polyploid cells with centrosomes did not require a SAC-based delay to divide when treated with CFI-402257." "Control cells had two tubulin-dense MTOCs visible before NEBD, acentrosomal cells only established two MTOCs well after NEBD and chromosome condensation." "Cells treated with both STLC and CFI-402257 formed monopolar spindles but then exited from mitosis, resulting in asymmetric division with extruded chromosomes."
Quotes
"The mitotic delay in acentrosomal cells is enforced by the SAC in a MPS1-dependent manner, and that a SAC-dependent mitotic delay is required for bipolar cell division to occur in acentrosomal cells." "Prevention of centrosome separation suffices to make cell division reliant on a SAC-dependent mitotic delay." "Centrosomes and their definition of two spindle poles early in mitosis provide a "timely two-ness" that allows cell division to occur in absence of a SAC-dependent mitotic delay."

Deeper Inquiries

What other cellular mechanisms or pathways might interact with the centrosome-SAC coordination to influence mitotic fidelity and cell division outcomes?

The centrosome-SAC coordination is crucial for ensuring accurate chromosome segregation and proper cell division. Several other cellular mechanisms and pathways may interact with this coordination to influence mitotic fidelity and cell division outcomes. One key player is the Aurora B kinase, which is known to regulate SAC and error-correction components. Aurora B kinase becomes enriched at kinetochores and chromosomes during mitosis, playing a critical role in ensuring proper attachment of chromosomes to the mitotic spindle. Additionally, the APC/C (Anaphase-Promoting Complex/Cyclosome) is another important player that maintains the spindle assembly checkpoint by targeting specific proteins for degradation. The APC/C is essential for regulating the timing of anaphase onset and ensuring accurate chromosome segregation. Furthermore, microtubule dynamics and motor proteins play a significant role in spindle assembly and chromosome movement during mitosis. Proteins like Eg5, a bipolar kinesin, are essential for spindle assembly and function. Disruption of Eg5 activity can lead to monopolar spindles and mitotic defects, highlighting the importance of microtubule dynamics in mitotic fidelity. Overall, the centrosome-SAC coordination interacts with a network of cellular mechanisms and pathways to ensure accurate chromosome segregation, proper spindle assembly, and timely cell division.

How might the findings on the role of centrosomes in temporal mitotic organization apply to the context of cancer cells, which often exhibit centrosome amplification or loss?

The findings on the role of centrosomes in temporal mitotic organization have significant implications for cancer cells, which frequently exhibit centrosome amplification or loss. In cancer cells, abnormalities in centrosome number and function can lead to mitotic defects, chromosome missegregation, and aneuploidy, all of which are hallmarks of cancer. Centrosome amplification, a common feature in many cancer types, can disrupt the normal bipolar spindle formation and lead to multipolar spindles during mitosis. This can result in chromosome segregation errors and genomic instability, contributing to tumor heterogeneity and progression. On the other hand, centrosome loss, as observed in acentrosomal cells, can also impact mitotic fidelity by altering the temporal organization of mitosis and delaying cell division. Understanding the role of centrosomes in mitotic organization can provide insights into the mechanisms underlying chromosome segregation errors and aneuploidy in cancer cells. Targeting centrosome-related pathways or mitotic regulators in cancer therapy could potentially exploit the vulnerabilities of cancer cells with centrosome abnormalities, offering new avenues for treatment strategies.

Could the insights into centrosome-SAC crosstalk inform the development of novel therapeutic strategies targeting mitotic regulators in cancer or other diseases?

The insights into centrosome-SAC crosstalk have the potential to inform the development of novel therapeutic strategies targeting mitotic regulators in cancer and other diseases. By understanding the intricate coordination between centrosomes and the SAC in ensuring accurate chromosome segregation and cell division, researchers can identify key molecular targets for therapeutic intervention. One potential therapeutic strategy could involve targeting mitotic regulators such as MPS1 kinase, which plays a crucial role in the SAC-mediated mitotic delay. Inhibiting MPS1 activity in cancer cells with centrosome abnormalities could disrupt the timely progression of mitosis, leading to mitotic arrest and cell death. This approach could selectively target cancer cells with centrosome amplification or loss while sparing normal cells. Additionally, targeting other components of the centrosome-SAC pathway, such as Aurora B kinase or APC/C, could also be explored as potential therapeutic targets. Modulating the activity of these regulators could disrupt mitotic progression in cancer cells, leading to cell cycle arrest or apoptosis. Overall, the insights into centrosome-SAC crosstalk provide a foundation for developing targeted therapies that exploit the vulnerabilities of cancer cells with mitotic defects, offering new opportunities for precision medicine in cancer treatment.
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