negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of intrinsic apoptotic signaling pathway in response to DNA damage. [GOC:BHF, GOC:mtg_apoptosis, GOC:rl, GOC:TermGenie, PMID:15314165]

Negative regulation of intrinsic apoptotic signaling pathway in response to DNA damage involves a complex interplay of cellular mechanisms designed to prevent premature and inappropriate cell death while ensuring appropriate elimination of damaged cells. This process is crucial for maintaining genomic integrity and preventing the development of diseases such as cancer. Here's a detailed breakdown of the key steps involved:

1. **DNA Damage Detection and Signaling:** Upon encountering DNA damage, cells activate a cascade of signaling pathways to sense and respond to the threat. Sensor proteins like ATM (Ataxia Telangiectasia Mutated) and ATR (ATM and Rad3-related) recognize DNA breaks and initiate a signaling cascade.

2. **Activation of Checkpoint Kinases:** ATM and ATR activate downstream kinases, including CHK1 and CHK2, which play a critical role in cell cycle arrest and DNA repair. This pause in the cell cycle allows time for DNA repair mechanisms to engage and attempt to repair the damaged DNA.

3. **Regulation of Pro-apoptotic Proteins:** The intrinsic apoptotic pathway, also known as the mitochondrial pathway, is a major cellular suicide program. Key players in this pathway include the Bcl-2 family proteins, which regulate mitochondrial outer membrane permeabilization (MOMP). DNA damage can trigger the activation of pro-apoptotic Bcl-2 family members like Bax and Bak, leading to MOMP and the release of pro-apoptotic factors from the mitochondria, such as cytochrome c.

4. **Apoptosis Inhibition:** In the context of DNA damage, the apoptotic cascade is tightly regulated to allow time for repair. Several mechanisms contribute to this negative regulation:

* **Activation of Anti-apoptotic Proteins:** DNA damage can also activate anti-apoptotic Bcl-2 family members like Bcl-2 and Bcl-xL. These proteins counteract the pro-apoptotic effects of Bax and Bak, preventing MOMP and the release of pro-apoptotic factors.
* **Regulation of Caspases:** Caspases are a family of proteases that execute the apoptotic program. DNA damage can trigger the activation of caspase inhibitors, such as XIAP (X-linked inhibitor of apoptosis protein), which prevent caspase activation and apoptosis.
* **DNA Repair Mechanisms:** The cell's DNA repair mechanisms work in parallel with apoptosis inhibition. If DNA damage can be successfully repaired, the cell can survive and continue to function normally.
* **Alternative Pathways:** If DNA damage is too severe or irreparable, cells can activate alternative pathways like senescence or autophagy to minimize potential harm to the organism.

5. **Outcome:** The decision between repair and apoptosis is a delicate balance. If DNA damage can be repaired effectively, the cell will survive. However, if the damage is extensive or irreparable, the cell will undergo apoptosis, preventing the transmission of damaged genetic material and potentially contributing to cancer development.

In summary, negative regulation of the intrinsic apoptotic signaling pathway in response to DNA damage is a complex and crucial process that allows cells to prioritize DNA repair over premature apoptosis, thus maintaining genomic integrity and cellular survival.'
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Proteins (5)

Compounds (43)