Cell cycle... Under Control.

Cell cycle checkpoints are control mechanisms that ensure the fidelity of cell division in eukaryotic cells. These checkpoints verify whether the processes at each phase of the cell cycle have been accurately completed before progression into the next phase. Multiple checkpoints have been identified, but some of them are less well understood than others.

An important function of many checkpoints is to assess DNA damage, which is detected by sensor mechanisms. When damage is found, the checkpoint uses a signal mechanism to either stall the cell cycle until repairs are made or, if repairs can't be made, to target the cell for destruction via apoptosis (effector mechanism). All the checkpoints that assess DNA damage appear to utilize the same sensor-signal-effector mechanism.

The cell cycle according to Temple and Raff, 1986, was meant to function as a clock, but if this was the case it would be expected that the stages of the cell cycle must function according to some sort of internal clock, that will determine how long a phase should take. Contradictorily, the cell cycle is now depicted like the falling dominoes, the preceding phase has to "fall" before the next phase can take place. The cell cycle checkpoints are therefore made up of composites of protein kinases and adaptor proteins which all play salient roles in the maintenance of the integrity of the division.

Checkpoints are now accepted to exist at every single point in the cell cycle. The DNA damage checkpoint is always active. Nonetheless, most human cells for example are terminally differentiated and must exit the cell cycle. There is a phase late in G₁ phase called the restriction point (RP, or the restriction checkpoint); cells that should cease division exit the cell cycle and enter G₀. Cells that continually divide in the adult human include hematopoietic stem cells and gut epithelial cells. The re-entrant into the cell cycle is therefore only possible by overcoming the RP. This is achieved by growth factor induced expression of cyclin D proteins. These then overcome the G₀ barrier and are able to enter the cell cycle.

The first checkpoint is located at the end of the cell cycle's G₁ phase, just before entry into S phase, making the key decision of whether the cell should divide, delay division, or enter a resting stage. Most cells stop at this stage and enter a resting state called G₀. Liver cells, for instance, only enter mitosis around once or twice a year. The G₁ checkpoint is where eukaryotes typically arrest the cell cycle if environmental conditions make cell division impossible or if the cell passes into G₀ for an extended period.

In animal cells, the G₁ phase checkpoint is called the restriction point, and in yeast cells it is called the start point. The restriction point is mainly controlled by action of the CKI- p16 (CDK inhibitor p16). This protein inhibits the CDK4/6 and ensures that it can no longer interact with cyclin D1 to cause the cell cycle progression. In growth induced or oncogenic induced cyclin D expression, this checkpoint is overcome because the increased expression of cyclin D allows its interaction with CDK4/6 by competing for binding. Once active CDK4/6-CYCLIN D complexes form, they phosphorylate the tumour suppressor retinoblastoma (Rb), this relieves the inhibition of the transcription factor E2F. E2F is then able to cause expression of cyclin E, which then interacts with CDK2 to allow for G1-S phase transition. That brings us to the end of the first checkpoint which allows the G0-G1-S-phase transition.

The second checkpoint is located at the end of G₂ phase, triggering the start of the M- phase (mitosis). In order for this checkpoint to be passed, the cell has to check a number of factors to ensure the cell is ready for mitosis. If this checkpoint is passed, the cell initiates the many molecular processes that signal the beginning of mitosis. The CDK's associated with this checkpoint are activated by phosphorylation of the CDK by the action of a "Maturation promoting factor" (or Mitosis Promoting Factor, MPF). The MPF activates the CDK in response to environmental conditions being right for the cell and allows the cell to begin DNA replication.

The molecular nature of this checkpoint involves an activating phosphatase, known as Cdc25, which under favourable conditions removes the inhibitory phosphates present within the MPF complex. However, DNA is frequently damaged prior to mitosis, and to prevent transmission of this damage to daughter cells, the cell cycle is arrested via inactivation of the Cdc25 phosphatase (via phosphorylation with other protein kinases).

The mitotic spindle checkpoint occurs at the point in metaphase where all the chromosomes have/should have aligned at the mitotic plate and be under bipolar tension. The tension created by this bipolar attachment is what is sensed and this is what initiates the anaphase entry. This sensing mechanism allows the degradation of cyclin B which harbours a D-box (destruction box). Degradation of cyclin B ensures it no longer inhibits the anaphase promoting complex, which in turn is now free to breakdown securin. The latter is a protein whose function is to inhibit separase, the protein composite which is responsible for the separation of sister chromatids. Once this inhibitory protein is degraded via ubiquitination and subsequent proteolysis, separin then causes sister chromatid separation. After the cell has split into its two daughter cells, the cell enters G₁.

When the genomic DNA of eukaryotic cells becomes damaged by spontaneous processes, chemical mutagens, or sunlight exposure, the replication of damaged DNA triggers a cellular response called a postreplication checkpoint. This response prevents cell cycle progression until postreplication repair processes are completed, and may control the activity of these DNA repair pathways. In cell types that execute S phase before mitosis, such as fission yeast and human cells, the postreplication checkpoint makes time for repair by delaying the onset of mitosis. In cell types where mitosis and S phase are concurrent, such as budding yeast, the postreplication checkpoint delays the progress of mitosis at metaphase.

The chk1 gene is required to mediate the postreplication checkpoint and is conserved in yeast and humans. Fission yeast cells in which the chk1 gene has been disrupted progress normally through the cell cycle after exposure to UV radiation until they have carried damaged DNA through S-phase and the subsequent mitosis, at which point cells begin to die and exhibit gross chromosomal damage. The BRCA1 tumor suppressor plays a role in the activation of human chk1, therefore the posreplication checkpoint may prevent the genetic changes that lead to cancer.

A number of genes required for the postreplication checkpoint encode proteins that recognize single-stranded DNA and the 5' end of transitions between single-stranded DNA and double-stranded DNA. These structure are known to be generated in two different ways during S phase. The replication of DNA containing damaged bases leaves gaps in the newly-synthesized DNA strand, and the replication of nicked or gapped DNA creates double-strand breaks. Both structures are thought to activate the postreplication checkpoint.

Source: Actually, the Wiki page.