(2)
2. Beskrive p53-DNA komplexet som et eksempel på protein-DNA interaktion. Angive at p53 inaktiverende muationer kan oftest lokaliseres i det DNA integrerende domæne
 Devlin, s. 391-2, fig. 9.28.a, c.
Devlin, s.217, clinical correlation 5.3

 

The p53 protein is also called a tumor suppressor protein. Its absence allows mutated DNA in the cell to accumulate, leading to its transformation to a cancer cell. 

Its main 3 functions are:

- the p53 protein is a transcription factor that controls the checkpoint between G1 and S phases of the cell cycle, and on sensing damaged DNA upregulates the expression of genes that inhibit cell division, to give the cell the time to repair the damaged DNA.

- it can also promote transcription of the DNA-repair genes.

- alternatively, it can instruct the cell to undergo apoptosis, if the DNA-damage is too extensive to repair.

All of these actions would counteract the neoplasmatic transformation of the cell.

The DNA-binding region of p53 consist of a central fold (similar to an immunoglobulin fold), made up of 2 beta-sheets with antiparallel strands.

This central fold provides the scaffolding (platform) for:

These motifs interact with DNA, in the following way:

p53 binds DNA as a tetramer. Each monomer of the tetramer binds to a discrete consensus target DNA. 

Mutant or interactive p53 forms are found in majority of human cells. Somatic mutations can be identified in about half of all human cancers. Mutations represent a loss of function, either affecting the stability of p53 or its DNA-binding ability.

Mutations found in p53 from tumors affect the DNA-binding domain of the protein. fx. nearly 20% of all mutated residues involve mutation at two positions of p53. Both mutated amino acids are arginines that form under normal circumstances H-bonds with DNA. This decreases the ability of p53 to regulate transcription.

fx.
Arginine in position 248 forms H-bonds with the minor groove of the DNA-helix with a tymine oxigen and a ring nitrogen of adenine. Mutation disrupts this H-bonded network and therefore the ability of p53 to regulate transcription.

 

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