How does the p53 tumour suppressor gene regulate the cell cycle?

The p53 tumor suppressor gene plays a critical role in safeguarding the integrity of the genome by controlling the cell cycle. It is often referred to as the "guardian of the genome" due to its essential function in preventing the propagation of damaged or mutated DNA, which is a key factor in cancer development. p53's regulation of the cell cycle is mainly focused on halting the cycle in response to DNA damage, thereby allowing time for repair or inducing apoptosis if the damage is irreparable. This process helps prevent the accumulation of mutations that could lead to tumor formation.

There are five key steps involved in how p53 regulates the cell cycle:

1. Detection of DNA Damage and Activation of p53

When a cell experiences DNA damage due to radiation, toxins, oxidative stress, or other reasons, certain kinases like ATM and ATR are activated. These kinases phosphorylate the p53 protein. Normally, p53 is degraded quickly by MDM2, but phosphorylation prevents this degradation, causing p53 to accumulate in the nucleus and become active.

2. Transcriptional Activation of p21 Gene

Once activated, p53 acts as a transcription factor. It binds to specific DNA sequences and activates the transcription of many genes. One of the most important genes it activates is CDKN1A, which produces p21 protein. p21 is a type of cyclin-dependent kinase inhibitor (CDKI).

3. Inhibition of Cyclin-CDK Complexes

p21 protein binds to Cyclin-CDK complexes, such as Cyclin E-CDK2, which are normally required for the transition from G1 phase to S phase of the cell cycle. By inhibiting these complexes, p21 stops the phosphorylation of Retinoblastoma protein (Rb), which in turn prevents the release of E2F transcription factors that are needed for DNA replication.

4. Cell Cycle Arrest at G1/S or G2/M Checkpoints

Due to the inhibition of Cyclin-CDK activity, the cell is arrested at either the G1/S or G2/M checkpoint, depending on the timing and location of the damage. This gives the cell sufficient time to repair damaged DNA. If the damage is repaired successfully, the cell cycle resumes normally.

5. Activation of Apoptosis if DNA Damage is Irreparable

If the DNA damage is beyond repair, p53 shifts its function and activates pro-apoptotic genes like BAX, PUMA, NOXA and others. These genes lead to programmed cell death (apoptosis). This ensures that severely damaged or potentially cancerous cells do not survive or divide.





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