The restriction point (or “point of no return”) is the most important checkpoint in the cell cycle. At this checkpoint, the cell self-evaluates its own replicative potential before deciding to either enter the S phase and the next round of cell division or to retire and leave the cell cycle. A cell that leaves the cycle in the G1 phase usually begins terminal differentiation by entering the GO phase (“O” stands for “outside” the cycle). Thus, the G1 phase may last for only a few hours (average 9 to 12 hours) in a rapidly dividing cell, or it may last a lifetime in a nondividing cell. This checkpoint is mediated by interactions between the retinoblastoma susceptibility protein (pRb) and a family of essential transcription factors (E2F) with target promoters. In normal cells, proper interaction between pRb and E2F turns off many genes and blocks cell-cycle progression.
In the S phase, DNA is replicated.
Initiation of DNA synthesis marks the beginning of the S phase, which is about 7.5 to 10 hours in duration. The DNA of the cell is doubled during the S phase, and new chromatids are formed that will become obvious at prophase or metaphase of the mitotic division. Chromosome replication is initiated at many different sites called replicons along the chromosomal DNA. Each replicon has a specifically assigned time frame for replication during S phase. Presence of the S DNA-damage checkpoint in this phase monitors quality of replicating DNA.
In the G2 phase, the cell prepares for cell division.
During this phase, the cell examines its replicated DNA in preparation for cell division. This is a period of cell growth and reorganization of cytoplasmic organelles before entering the mitotic cycle. The G2 phase may be as short as 1 hour in rapidly dividing cells or of nearly indefinite duration in some polyploid cells and in cells such as the primary oocyte that are arrested in G2 for extended periods. Two checkpoints monitor DNA quality: the G2 DNA-damage checkpoint and the unreplicated-DNA checkpoint. The latter checkpoint prevents the progression of the cell into the M phase before DNA synthesis is complete.
Mitosis occurs in the M phase.
Mitosis nearly always includes both karyokinesis (division of the nucleus) and cytokinesis (division of the cell) and lasts about 1 hour. Mitosis takes place in several stages described in more detail below. Separation of two identical daughter cells concludes the M phase. The M phase possesses two checkpoints: the spindle-assembly checkpoint, which prevents premature entry into anaphase, and the chromosome-segregation checkpoint, which prevents the process of cytokinesis until all of the chromosomes have been correctly separated.
The mitotic catastrophe caused by malfunction of cell-cycle checkpoints may lead to cell death and tumor cell development.
Malfunction of any of the three DNA-damage checkpoints at the G1, S, and G2 phases of the cell cycle and the spindle-assembly checkpoint at M phase may lead to a mitotic catastrophe. Mitotic catastrophe is defined as the failure to arrest the cell cycle before or at mitosis, resulting in aberrant chromosome segregation. Under normal conditions, death in these cells will occur by activation of the apoptotic cycle.
Cells that fail to execute the apoptotic cycle in response to DNA or mitotic spindle damage are likely to divide asymmetrically in the next round of cell division. This leads to the generation of aneuploid cells (cells containing abnormal chromosome numbers). Thus, a mitotic catastrophe may be regarded as one of the mechanisms contributing to oncogenesis (tumor cell development).