Question

What is p53’s role in the cell, and why is it so heavily modified?

Answer 1

p53 - "GUARDIAN ANGEL OF THE GENOME"

• Because of their roles in functions like DNA repair,cell growth arrest and apoptosis they are regarded as the guardian angel of the genome.
• Example for a TSG (Tumor Suppressor Gene) - i.e. It's activity can prevent the formation of tumors.
• This gene is located in 17p13.
• Discovered in the year 1979.
• p53 gene codes for p53 protein.
• They are located in almost all tissues ,unstable ;hence degrades easily.
• In cancer this is the gene that is commonly mutated.
• Functions include ; regulation of cell cycle,DNA repair and apoptosis.
• They prevent formation of tumors either by arresting cell growth / by stimulating apoptosis.
• When a DNA is damaged,our body recognizes it and triggers the expression of p53 gene;which causing the production of p53 protein.This increased p53 levels prevents the cell from entering the S phase of the cell cycle.Thus the cell cycle halts and the damaged DNA is prevented from replication,which ultimately prevents the production of faulty cells with damaged DNA.The damaged DNA is either repaired / permanently arrested.
• The other important role of p53 is repairing damaged DNA - p53 induces DNA repair genes and if the DNA can be repaired,the p53 automatically degrades after the repairing process,and the repaired DNA goes for replication which was earlier arrested by p53.If the repairing process fails then the damaged DNA is permanently arrested /undergoes senescence(Apoptosis).
• p53 altogether by their functions conserves stability.
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• In a normal cell p53 exists in inactivated form.p53 is inactivated by mdm2 as shown in the figure above.mdm2 is the negative regulator of p53.When an unusual activity like DNA damage / any other stress thus mdm2 will be dissociated from p53 leading to the activation of p53.
• Regulation of p53

In normal conditions ; p53 concentration are always kept low by continuous degradation.The reason for this tight regulation is if in case any mishap happens it will totally affects the body equilibrium .As we all know cells in our body is continuously dividing depending on the needs.Cell growth and cell death are always maintained properly ,any imbalance in the regulation of p53 can disrupt this balance.

• Mdm2 also acts as ubiquitin ligase;covalently attaches to p53 and thus marking p53 for its degradation by proteasome. This Ubiquitylation is reversible. A ubiquitin specific protease, USP7 , can cleave ubiquitin off p53, thus protecting it from proteasome-dependent degradation. One of the ways in which p53 is stabilized in response to oncogenic insults. Phosphorylation of the N-terminal end of p53 by the above- mentioned protein kinases disrupts Mdm2-binding.