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Mitosis in vertebrates: the G2/M and M/A transitions and their associated checkpoints
1Division of Translational Medicine, New York State Department of Health, Wadsworth Center, C-200 Biggs Laboratory, P.O. Box 509, Albany, NY 12201-0509, USA. rieder@wadsworth.org
Abstract:
In this review, I stress the importance of direct data and accurate terminology when formulating and communicating conclusions on how the G2/M and metaphase/anaphase transitions are regulated. I argue that entry into mitosis (i.e., the G2/M transition) is guarded by several checkpoint control pathways that lose their ability to delay or stop further cell cycle progression once the cell becomes committed to divide, which in vertebrates occurs in the late stages of chromosome condensation. After this commitment, progress through mitosis is then mediated by a single Mad/Bub-based checkpoint that delays chromatid separation, and exit from mitosis (i.e., completion of the cell cycle) in the presence of unattached kinetochores. When cells cannot satisfy the mitotic checkpoint, e.g., when in concentrations of spindle poisons that prohibit the stable attachment of all kinetochores, they are delayed in mitosis for many hours. In normal cells, the duration of this delay depends on the organism and ranges from ∼4 h in rodents to ∼22 h in humans. Recent live cell studies reveal that under this condition, many cancer cells (including HeLa and U2OS) die in mitosis by apoptosis within ∼24 h, which implies that biochemical studies on cancer cell populations harvested in mitosis after a prolonged mitotic arrest are contaminated with dead or dying cells.
Insights
Accurate terminology is crucial for understanding cell cycle regulation. Cancer cells undergoing prolonged mitotic arrest may die, contaminating biochemical studies.
Area of Science:
- Cell Biology
- Molecular Biology
- Genetics
Background:
- Cell cycle checkpoints, particularly the G2/M and mitotic checkpoints, are critical for maintaining genomic stability.
- The G2/M transition is regulated by checkpoints that delay cell cycle progression until key events are completed.
- The mitotic checkpoint (spindle assembly checkpoint) ensures proper chromosome alignment before anaphase onset.
Purpose of the Study:
- To emphasize the importance of precise data and terminology in cell cycle regulation research.
- To clarify the mechanisms governing the G2/M and metaphase/anaphase transitions.
- To highlight the implications of mitotic arrest duration and cell death in cancer cells for experimental design.
Main Methods:
- Review of existing literature on cell cycle regulation and checkpoint control.
- Analysis of data from live cell studies on cancer cell behavior during mitotic arrest.
- Discussion of the impact of prolonged mitotic arrest on cell viability and experimental outcomes.
Main Results:
- Vertebrate cells commit to mitosis during late chromosome condensation, after which checkpoints lose their ability to halt progression.
- The Mad/Bub-based checkpoint delays chromatid separation until all kinetochores are attached.
- Prolonged mitotic arrest, induced by spindle poisons, leads to cell death by apoptosis within approximately 24 hours in many cancer cells.
Conclusions:
- Accurate terminology and direct data are essential for understanding cell cycle regulation, specifically the G2/M and metaphase/anaphase transitions.
- Cancer cells undergoing prolonged mitotic arrest are prone to apoptosis, which can confound biochemical studies.
- Experimental protocols involving mitotic arrest in cancer cells must account for cell death to ensure data integrity.
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