How does p53 halt the cell cycle?

The p53 protein is a powerful tumour suppressor and transcription factor. It plays a very important role in protecting the cell from uncontrolled division. Whenever the cell experiences DNA damage, hypoxia, or stress signals, the p53 protein gets activated. However, it does not directly stop the cell cycle machinery. Instead, it halts the cell cycle indirectly by activating other genes that code for CDK inhibitors, especially p21 (Cip1/Waf1). This action ensures that the damaged cell does not move forward in the cell cycle until the issue is fixed.

Mechanism of Cell Cycle Arrest by p53

The mechanism through which p53 halts the cell cycle involves several key steps, which are explained below:

1. DNA Damage Sensing and p53 Activation

  • When DNA damage occurs, sensor proteins like ATM (Ataxia Telangiectasia Mutated) and ATR (ATM and Rad3-related) detect the problem. These proteins activate Chk1 and Chk2 kinases, which then phosphorylate and stabilize p53. Under normal conditions, p53 is unstable because it is continuously degraded by MDM2, but upon phosphorylation, p53 becomes stable and active.

2. Transcriptional Activation of p21

  • Once stabilized, p53 works as a transcription factor. It enters the nucleus and binds to the promoter region of the CDKN1A gene, which encodes p21. This causes high production of p21 protein in the cell.

3. Role of p21 in Halting the Cell Cycle

  • p21 protein belongs to the Cip/Kip family of CDK inhibitors. It directly binds to Cyclin-CDK complexes, especially Cyclin E-CDK2 and Cyclin A-CDK2, and inhibits their kinase activity. These complexes are necessary for G1 to S phase progression. When they are inhibited, the cell cannot proceed to DNA replication.

4. G1 Arrest (and Sometimes G2 Arrest)

  • In most cases, p53 causes G1 phase arrest by stopping Cyclin E-CDK2. In some conditions, it may also help in G2 arrest by inhibiting Cyclin B-CDK1 through other mediators like 14-3-3σ. This gives time for DNA repair and avoids the passing of mutations to daughter cells.






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