Which proteins regulate the progression from G1 to S phase?

In eukaryotic cells, the transition from G1 to S phase of the cell cycle is one of the most important and carefully regulated steps. This phase decides whether a cell will proceed toward DNA replication or stay in a resting state (G₀ Phase) or even go for repair. Cells make this decision based on internal and external signals, and this entire decision making process is controlled by specific regulatory proteins.

There are five main types of protein regulators that play a central role in G1 to S phase transition. These proteins work in coordination and any disturbance in their function can lead to abnormal cell division or diseases like cancer.

1. Cyclins (Cyclin D and Cyclin E)

Cyclins are regulatory proteins that appear and disappear during different phases of the cell cycle. During the early G1 phase, Cyclin D is produced in response to external signals like growth hormones or mitogens. It binds to CDK4 and CDK6, forming active complexes that start phosphorylating various target proteins and push the cell forward in the G1 phase.

Later, in the late G1 phase, Cyclin E starts getting expressed. It binds to CDK2 and this Cyclin E-CDK2 complex is very important for the actual commitment of the cell to enter S phase. Without the Cyclin E-CDK2 complex, the cell cannot cross the G1 checkpoint.

2. Cyclin-Dependent Kinases (CDKs)

CDKs are enzymes that need to bind with cyclins to become active. They do not function alone. The main CDKs active in the G1 to S transition are CDK4, CDK6 and CDK2.
  • CDK4 and CDK6 become active after binding with Cyclin D
  • CDK2 becomes active after binding with Cyclin E
These active CDK-cyclin complexes phosphorylate target proteins, mainly the retinoblastoma protein (Rb), which acts like a brake on the cell cycle.

3. Retinoblastoma Protein (Rb)

The retinoblastoma protein (Rb) protein is a tumour suppressor protein. In its original, unphosphorylated form, Rb binds to a transcription factor called E2F and prevents it from activating genes required for DNA replication.

Once Rb is phosphorylated by the CDK4/6-Cyclin D and CDK2-Cyclin E complexes, it undergoes a change in shape and releases E2F. This release is the key signal that allows the cell to move from G1 into S phase and begin DNA synthesis.

4. E2F Transcription Factor

E2F plays a very important role in initiating the S phase. Once freed from Rb, it starts the transcription of many genes that are essential for the S phase. These include genes for DNA polymerases, nucleotide synthesis enzymes and histone proteins.

Without active E2F, the S phase cannot begin. Thus, E2F acts like a master switch that turns on the machinery needed for DNA replication.

5. CDK Inhibitors (CKIs)

These proteins work as brakes or checkpoints. If the cell has DNA damage or is not ready for replication, CDK inhibitors will stop the activity of CDK-cyclin complexes. Some common CKIs are p21, p27 and p16.

For example, in response to DNA damage, the protein p53 activates the transcription of p21, which then binds to and inhibits the Cyclin E-CDK2 complex, stopping the cell from entering S phase. This gives the cell time to repair itself before continuing.




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