Cyclins are a family of proteins that control the progression of cells through the cell cycle by activating cyclin-dependent kinase (CDK) enzymes. This set of notes will delve into their role in cell cycle regulation, their interaction with CDKs, and the control of cell cycle checkpoints.

Role in Cell Cycle Regulation

Cyclins are pivotal to the cell cycle. They dictate the progression and order of cell cycle events, ensuring that the processes of the cell cycle occur in an orderly and regulated manner. They achieve this through their unique ability to activate CDKs, which in turn phosphorylate various proteins essential for the cell cycle.

Cyclins are classified into four main types based on their function in the cell cycle - G1 cyclins, G1/S cyclins, S cyclins, and M cyclins. The concentration of these cyclins rises and falls as the cell progresses through the cycle, and the different cyclins peak in concentration at different times. This cyclical pattern is responsible for their name - cyclins.

• G1 Cyclins - These cyclins accumulate in late G1 and promote the cell's progression into the S phase. Their role is to ensure the cell is ready to commit to DNA replication.
• G1/S Cyclins - These cyclins build up in the G1 phase and commit the cell to DNA synthesis in the S phase. They help to trigger the processes necessary for the synthesis phase.
• S Cyclins - The S cyclins bind to CDKs during the S phase and oversee the replication of DNA. They remain associated with the replication origins to prevent re-initiation of replication.
• M Cyclins - These cyclins promote the initiation of mitosis. They are degraded by the anaphase-promoting complex (APC), a ubiquitin ligase, towards the end of mitosis, allowing for the exit from mitosis and the initiation of the next cell cycle.

The production and destruction of cyclins is a tightly regulated process. As the cell progresses into a new phase, new cyclins are synthesised and existing ones are destroyed. The degradation of cyclins is carried out by the proteasome, the cell's protein degradation machinery, which ensures that cyclins don't linger in the cell once their job is done.

Interaction with Cyclin-Dependent Kinases (CDKs)

Cyclin-Dependent Kinases (CDKs) are a group of protein kinases first discovered for their role in regulating the cell cycle. They are dependent on the binding of cyclin to be active, hence the name.

CDKs are always present within the cell but remain inactive until they bind with the appropriate cyclin. This binding changes the shape of the CDK in a way that activates the enzyme. Once active, the cyclin-CDK complexes can phosphorylate specific proteins, thereby controlling their activity and the progression of the cell cycle.

Phosphorylation changes the target protein's structure, altering its interaction with other proteins, its stability, and its activity. The specific effect on the target protein depends on which amino acid residue is phosphorylated, the number of phosphates added, and the 3D context in which the phosphorylation occurs.

For instance, the active cyclin E-CDK2 complex phosphorylates a set of proteins required for DNA synthesis, thereby initiating the S phase. Likewise, cyclin B-CDK1 phosphorylates various proteins involved in nuclear envelope breakdown, chromosomal condensation, and spindle pole assembly, thereby initiating the M phase.

In this way, cyclins and CDKs regulate each phase's timing and progression, ensuring that each process is completed before the next one begins. In essence, the CDK-cyclin complexes act as the cell cycle's 'clock', telling the cell when it is time to progress to the next phase.

Control of Cell Cycle Checkpoints

Cell cycle checkpoints are surveillance mechanisms that monitor the order, integrity, and fidelity of the major events of the cell cycle. These checkpoints verify whether the processes at each phase of the cell cycle have been accurately completed before progressing into the next phase.

Cyclins and CDKs are essential in these checkpoint controls. They work to ensure that the cell only progresses to the next phase of the cell cycle when it is ready. If damage or error is detected at any checkpoint, cell cycle progression is halted, and the error is repaired. If the error is irreparable, the cell may undergo programmed cell death or apoptosis.

• G1 Checkpoint - This checkpoint, also known as the 'restriction point', is where the cell verifies the DNA's integrity before committing to S phase. This is considered a point of no return as the cell usually completes the cell cycle and divides once it passes this checkpoint unless a halt is called at a later checkpoint due to DNA damage. The CDK4/6-cyclin D and CDK2-cyclin E complexes are key in passing this checkpoint.
• S Phase Checkpoint - This ensures that all the DNA has been correctly replicated without any errors. This checkpoint also prevents the replication of damaged DNA. CDK2-cyclin A complex plays an essential role here.
• G2 Checkpoint - Here, the cell confirms it has correctly replicated the DNA and is ready for mitosis. CDK1-cyclin B complex is vital for passing this checkpoint.
• M Phase Checkpoint - This checkpoint ensures that all chromosomes are properly attached to the spindle before anaphase. This prevents the segregation of chromosomes until they are properly aligned, thus ensuring that each daughter cell receives a full set of chromosomes. CDK1-cyclin B complex again plays a significant role.