Question

explain how DNA damamge activates p53 and the effects of p53 activation that prevents the division and survival of damamged cells. focus on the interactions between key proteins and on the major effect of activation of the p53 pathway.

Answer 1

DNA damamge activates p53 and the effects of p53 activation that prevents the division and survival of damamged cells is explained as follows:-

In normal cells, the p53 protein level is low.

DNA damage and other stress signals may trigger the increase of p53 proteins, which have three major functions: growth arrest, DNA repair and apoptosis (cell death).

The growth arrest stops the progression of cell cycle, preventing replication of damaged DNA. During the growth arrest, p53 may activate the transcription of proteins involved in DNA repair.

Apoptosis is the "last resort" to avoid proliferation of cells containing abnormal DNA.

The cellular concentration of p53 must be tightly regulated. While it can suppress tumors, high level of p53 may accelerate the aging process by excessive apoptosis.

The major regulator of p53 is Mdm2, which can trigger the degradation of p53 by the ubiquitin system.

Mechanism of Regulation of p53.

(a) Expression of Mdm2 is activated by p53.

(b) Binding of p53 by Mdm2 can trigger the degradation of p53 via the ubiquitin system.

(c) Phosphorylation of p53 at Ser15, Thr18 or Ser20 will disrupt its binding with Mdm2. In normal cells, these three residues are not phosphorylated, and p53 is maintained at low level by Mdm2.   

(d) DNA damage may activate protein kinase (such as ATM, DNA-PK, or CHK2) to phosphorylate p53 at one of these three residues, thereby increasing p53 level. Since Mdm2 expression is activated by p53, the increase of p53 also increases Mdm2, but they have no effect while p53 is phosphorylated. After the DNA damage is repaired, the ATM kinase is no longer active. p53 will be quickly dephosphorylated and destroyed by the accumulated Mdm2.

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