Why p53 is called p53 guardian of the genome?
Also called as the “policeman of the oncogenes” referring to its role in conserving stability by preventing genome mutation.
What are Tumor suppresser genes?
- Tumor suppresser genes: Genes that acts as ‘cell brakes’ that encode proteins that restrict cell division and growth and protect from becoming malignant. Eg: p53, RB, BRCA1, P16 etc
- Mutation of p53 is very common in many types of cancers indicating the significance of a functional p53 gene.
The human p53 gene is located on the seventeenth chromosome (17p13.1).
The image shows a tetramer of the p53 DNA-binding domain complexed with DNA. The tetramer subunits are shown as light blue, green, orange, and yellow ribbons, with red spheres marking several major "hot spots" of mutation. The DNA is shown in purple and blue with simplified sugars and bases.
The p53 protein is a phosphoprotein made of 393 amino acids. It consists of four units (or domains):
- A domain that activates transcription factors.
- A domain that recognizes specific DNA sequences (core domain).
- A domain that is responsible for the tetramerization of the protein.
- A domain that recognized damaged DNA, such as misaligned base pairs or single-stranded DNA.
- Cell cycle arrest during G1/S and G2/M arrest in cells with damaged DNA: mediated by p21, a cdk inhibitor that is essential for progression from G1 to S phase.
- Apoptosis: If the DNA repair system fails to correct the damaged DNA, p53 trigger such cells to undergo apoptosis. Mediators are proapopotic proteins like Bax, Apaf-1, PUMA and NoxA.
- Structural basis of restoring sequence-specific DNA binding and transactivation to mutant p53 by suppressor mutations. Suad O, Rozenberg H, Brosh R, Diskin-Posner Y, Kessler N, Shimon LJ, Frolow F, Liran A, Rotter V, Shakked Z. J Mol Biol. 2009 Jan 9;385(1):249-65.
- Structural basis of DNA recognition by p53 tetramers. Kitayner M, Rozenberg H, Kessler N, Rabinovich D, Shaulov L, Haran TE, Shakked Z. Mol Cell. 2006 Jun 23;22(6):741-53.