Cell cycle is a series of events that take place when a cell decides to divide. These events in the cell cycle need regulation , therefore the progression of cells through cell cycle is controlled by checkpoints at different stages. Any defect in the cell, such as a damaged DNA can make the cell enter the interphase until the damage is corrected. As discussed in my earlier blog , a cell predominantly has three major checkpoints.
G1 checkpoint, G2 checkpoint and the M checkpoint . The cells enters the cell cycle where they divide and double in volume. Every aspect is checked by the cells internal mechanism making sure that the cell is ready for division. Upon entering the cell cycle, the checkpoints make sure that the cell has all the necessary factors to proceed to the next phase of cell division. MPF , also known as maturation promoting factor plays a significant role in this. Cyclin and CDK together make the MPF, which help the cell cross each checkpoint.
CYCLINS AND CDKs
To understand cell cycle regulation, these factors have to be understood first. Cyclins and cdks are evolutionary concerned proteins that work together
Cyclins are group of related proteins that are activated by cyclin dependent kinases, and they together help the cell cross checkpoints. There are four types of cyclins involved in cell cycle regulation ,cyclin A, cyclin B, cyclin D and cyclin E. The level of each cyclin fluctuates according to the phase of the cell cycle. Cyclins regulate cell cycle only when attached to cdks and to be fully active they must be phosphorylated at specific locations.
cdks are important regulators of all cell cycle. They phosphorylate either S or T amino acids thereby regulating the activity of those proteins. Animals have a total of 9 CDKs of which four are really critical to the cell cycle.
CDKs require ATP to perform phosphorylation. They have an ATP binding cleft , to which the binding of ATP is regulated by 2 mechanisms.
- The Cdks have a flexible T loop which has threonine (T) residue , which normally blocks the ATP binding cleft, but not when the threonine is phosphorylated.
- Or the cyclins bind Cdks which also expose the ATP binding cleft. Therefore a fully active is one which is both phosphorylated at the Threonine on the T loop and is bound to a cyclin.
CELL CYCLE REGULATION
Cell cycle is regulated in two ways
- Positive regulation- which involves cyclins and cyclin dependent kinases.
- Negative regulation- which involves Retinoblastoma protein (Rb), p53 and p21.
p53 is a multifunctional protein which is activated during G1 phase of the cell cycle. when damages are detected during the G1 phase p53 recruits repair enzymes. If not it triggers apoptosis.p53 acts by triggering p21 which also plays a very important role in cell cycle regulation. The function of p21 is to bind to cyclin CDK complex, thereby halting the cell cycle and preventing the cell from entering the S phase.p53 and p21 are also known as tumor suppressor genes.
As we have discussed cell cycle is controlled by cyclins and CDKs . Cell cycle controlled by tumor suppressors, Transcription genes, proteins, enzyme and signaling molecules.
Gene E2F is responsible for regulating the expression of transcription genes and CDK2, cyclin E and cyclin F.As mentioned earlier, in case of DNA damage p53 stimulates the production on p21 which then binds to the cyclin CDK complex and leads to the arrest of cell cycle. The cells are arrested in this phase until the DNA damage is repaired and the p21 levels drop. The tumor suppressor pRb inhibits the expression of E2F gene.
Cyclin D CDK4 complex and cyclin D CDK 6 complex phosphorylate pRb that leads to the inactivation of Rb protein and E2F is expressed. Expression of E2F gene in turn causes the expression of transcription genes and formation of cyclin Ecdk2 complex which pushes the cell into the S phase.
The most important task performed by the cell s in the S phase is DNA synthesis. Cyciln A CDK2 complex is needed for DNA synthesis by the cell during the S phase causing it’s levels to increase during this phase of the cell cycle. Whereas cyclin A CDK1 and Cyclin B cdk1 promote the events involved in the m phase.
Towards the end of mitosis, APC causes the Ubiquitination and destruction of cyclin A CDK1 and Cyclin B CDK1 which ultimately leads to the termination of M phase.
APC/C is an enzyme that works by adding protein tags called ubiquitin(Ub) to their targets. Once the target is tagged with ubiquitin, the proteasomes attack and destroy it. In a similar way, APC/C attaches Ub tag to M cyclin, causing them to be chopped by proteasomes, allowing the daughter cells to enter G1 phase.
The role of APC/C in separation of sister chromatids during anaphase
- APC/C first adds the ubiquitin tag to securin ,leading to its destruction be proteasome. Securin normally binds to a protein separase and inactivates it. However, in the absence of securin, separase gets activated.
- The activated separse then chops cohesin that holds sister chromatids together allowing them to seperate.