The essential processes of the cell cycle—such as DNA replication, mitosis, and cytokinesis—are triggered by a cell-cycle control system. By analogy with a washing machine, the cell-cycle control system is shown here as a central arm—the controller— that rotates clockwise, triggering essential processes when it reaches specific points on the outer dial.mitosis cytokinesis cell-cycle control systemcell-cycle control system

How might one design a control system that safely guides the cell through the events of the cell cycle? A clock, or timer, that turns on each event at a specific time, thus providing a fixed amount of time for the completion of each event. A mechanism for initiating events in the correct order; entry into mitosis, for example, must always come after DNA replication. A mechanism to ensure that each event is triggered only once per cycle. Binary (on/off) switches that trigger events in a complete, irreversible fashion. It would clearly be disastrous, for example, if events like chromosome condensation or nuclear envelope breakdown were initiated but not completed. Robustness: backup mechanisms to ensure that the cycle can work properly even when parts of the system malfunction. Adaptability, so that the system's behavior can be modified to suit specific cell types or environmental conditions.

Information about the completion of cell-cycle events, as well as signals from the environment, can cause the control system to arrest the cycle at specific checkpoints. The most prominent checkpoints occur at locations marked with yellow boxes.

Checkpoints Generally Operate Through Negative Intracellular Signals Checkpoint mechanisms like those just described tend to act through negative intracellular signals that arrest the cell cycle, rather than through the removal of positive signals that normally stimulate cell-cycle progression.

The Cell-Cycle Control System Is Based on Cyclically Activated Protein Kinases cyclin-dependent kinases (Cdks). The activity of these kinases rises and falls as the cell progresses through the cycle. The oscillations lead directly to cyclical changes in the phosphorylation of intracellular proteins that initiate or regulate the major events of the cell cycle—DNA replication, mitosis, and cytokinesis.

Cell cycle controls – cyclins regulatory proteins levels cycle in the cell – Cdks cyclin-dependent kinases phosphorylates cellular proteins – activates or inactivates proteins – Cdk-cyclin complex triggers passage through different stages of cell cycle

Cdk associates successively with different cyclins to trigger the different events of the cycle. Cdk activity is usually terminated by cyclin degradation. For simplicity, only the cyclins that act in S phase (S-cyclin) and M phase (M-cyclin) are shown, and they interact with a single Cdk; as indicated, the resulting cyclin-Cdk complexes are referred to as S-Cdk and M-Cdk, respectively.

There are four classes of cyclins, each defined by the stage of the cell cycle at which they bind Cdks and function. Three of these classes are required in all eucaryotic cells: 1. G1/S-cyclins bind Cdks at the end of G1 and commit the cell to DNA replication. 2. S-cyclins bind Cdks during S phase and are required for the initiation of DNA replication. 3. M-cyclins promote the events of mitosis. In most cells, a fourth class of cyclins, the G1-cyclins, helps promote passage through Start or the restriction point in late G1

Cdk Activity Can Be Suppressed Both by Inhibitory Phosphorylation and by Inhibitory Proteins The rise and fall of cyclin levels is the primary determinant of Cdk activity during the cell cycle. Several additional mechanisms, however, are important for fine-tuning Cdk activity at specific stages in the cell cycle. The activity of a cyclin-Cdk complex can be inhibited by phosphorylation at a pair of amino acids in the roof of the active site. Phosphorylation of these sites by a protein kinase known as Wee1 inhibits Cdk activity, while dephosphorylation of these sites by a phosphatase known as Cdc25 increases Cdk activity.

Cyclin-Cdk complexes can also be regulated by the binding of Cdk inhibitor proteins (CKIs). There are a variety of CKI proteins, and they are primarily employed in the control of G1 and S phase. The three-dimensional structure of a cyclin-Cdk-CKI complex reveals that CKI binding dramatically rearranges the structure of the Cdk active site, rendering it inactive

Cell-cycle control depends crucially on at least two distinct enzyme complexes that act at different times in the cycle to cause the proteolysis of key proteins of the cell-cycle control system, thereby inactivating them. The Cell-Cycle Control System Depends on Cyclical Proteolysis

Cell-Cycle Control Also Depends on Transcriptional Regulation Post-transcriptional modifications regulate activation and inactivation of proteins

External Signals

Summary The central components of the cell-cycle control system are cyclin- dependent protein kinases (Cdks), whose activity depends on association with regulatory subunits called cyclins. Oscillations in the activities of various cyclin-Cdk complexes leads to the initiation of various cell-cycle events. Thus, activation of S- phase cyclin-Cdk complexes initiates S phase, while activation of M- phase cyclin-Cdk complexes triggers mitosis. The activities of cyclin-Cdk complexes are influenced by several mechanisms, including phosphorylation of the Cdk subunit, the binding of special inhibitory proteins (CKIs), proteolysis of cyclins, and changes in the transcription of genes encoding Cdk regulators. Two enzyme complexes, SCF and APC, are also crucial components of the cell-cycle control system; they induce the proteolysis of specific cell-cycle regulators by ubiquitylating them and thereby trigger several critical events in the cycle.