positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator

Definition

Target type: biologicalprocess

Any process that activates or increases the frequency, rate or extent of intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator. [GOC:TermGenie, PMID:17719541]

The p53 protein, a tumor suppressor, plays a critical role in the cellular response to DNA damage by initiating apoptosis, a programmed cell death process. When DNA damage is detected, p53 activates a complex signaling cascade that leads to the activation of pro-apoptotic proteins, ultimately culminating in the dismantling of the cell. Here's a detailed breakdown of the process:

1. **DNA Damage Recognition:** p53 is typically kept in a low concentration within the cell, bound by its negative regulators. Upon DNA damage, the DNA damage response (DDR) pathway is activated. Sensor proteins like ATM and ATR detect the damage and phosphorylate p53, leading to its stabilization and activation.
2. **p53 Activation and Transcriptional Regulation:** Activated p53 acts as a transcription factor, binding to specific DNA sequences called p53 response elements (p53REs) located in the promoter regions of target genes. p53 then initiates the transcription of numerous pro-apoptotic genes, including:
* **Bax:** Bax is a pro-apoptotic protein that forms pores in the mitochondrial membrane, leading to the release of cytochrome c.
* **Puma and Noxa:** These proteins are BH3-only proteins that activate Bax and Bak, other pro-apoptotic proteins, by directly binding to their BH3 domains.
* **Apaf-1:** Apaf-1 is an adaptor protein that assembles with cytochrome c to form the apoptosome, a crucial platform for caspase activation.
3. **Mitochondrial Apoptosis Pathway Activation:** Once the apoptotic cascade is initiated, Bax and Bak form pores in the mitochondrial membrane, disrupting its integrity and leading to the release of cytochrome c into the cytosol.
4. **Caspase Activation and Cell Death Execution:** Cytochrome c binds to Apaf-1, activating it and triggering the formation of the apoptosome. The apoptosome then recruits and activates caspase-9, an initiator caspase. This sets off a cascade of caspase activation, leading to the activation of effector caspases such as caspase-3 and -7. These effector caspases cleave various cellular substrates, dismantling the cell and ultimately leading to apoptosis.

In summary, p53, a p53 class mediator, acts as a critical regulator of intrinsic apoptotic signaling pathway in response to DNA damage. Its activation triggers a cascade of events involving pro-apoptotic protein expression, mitochondrial dysfunction, caspase activation, and ultimately, the dismantling of the cell to prevent the propagation of damaged DNA.'
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Proteins (1)

Compounds (2)