Asked Dec 7, 2019

Describe the ATM-p53 repair pathway in normal cells and cancerous cells


Expert Answer

Step 1

Apoptosis is a genetically controlled mechanism of cell death, which is important for the elimination of unwanted cells for normal development and maintenance of tissue homeostasis. One of the major apoptosis signaling pathways involves the p53 tumor suppressor. 

Step 2

Tumor protein p53 is a nuclear transcription factor that regulates the expression of a wide variety of genes involved in apoptosis or senescence in response to genotoxic or cellular stress. There are four conserved domains in p53. They are the N-terminal domain that is required for transcriptional transactivation, a sequence-specific DNA binding domain, a tetramerization domain near the C-terminal end, and a C-terminal domain that interacts directly with single-stranded DNA. p53 is normally maintained at low levels by continuous ubiquitylation and subsequent degradation by the 26S proteasome. In this process, posttranslational modifications of p53 such as phosphorylation and acetylation play important roles in the stability of p53, possibly through modulating ubiquitination by MDM2 ubiquitin ligase. The N-terminal transactivation domain of p53 has several key phosphorylation sites. Phosphorylation near the MDM2 binding sites has been believed to reduce the affinity between p53 and MDM2 and therefore cause the stabilization of p53. In fact, activated ATM/ATR and Chk1/2 phosphorylate the serine 15 and 20 residues, respectively, which lie right under the binding pocket of MDM2. These phosphorylations disrupt the binding with MDM2, resulting in stabilization of p53. The main kinases involved in p53 phosphorylation include Chk1 (Cell Cycle Checkpoint Kinase-1) and Chk2 (Cell Cycle Checkpoint Kinase-2). This event results in either apoptosis or cell cycle arrest. 

Step 3

When the cell is confronted with stress like DNA damage, hypoxia, cytokines, metabolic changes, viral infection, or oncogenes, however, p53 ubiquitylation is suppressed and p53 is stabilized and accumulates in the nucleus. In response to DNA damage, Chk1 and Chk2, activated by ATR and ATM, respectively, phosphorylate p53. When the cell returns to its normal state following DNA repair, p53 needs to be simultaneously reduced.

Mutant p53 forms the hetero-oligomers with wild-type p53 through their intact oligomerization domains and acts as a dominant-negative inhibitor toward wild-type p53. In contrast to short-lived wild-type p53, mutant p53 has a prolonged half-life with oncogenic potential. The accumulating eviden...


Image Transcriptionclose

Cell cycle arrest DNA damage p21 Enorgalie Enangitia slrere Wild-type Mutant p53 p53 PUMA BAX -myc)(TERT APOPTOSIS ONCOGENESIS


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