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

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. [GOC:BHF, GOC:mtg_apoptosis, GOC:rl, GOC:TermGenie, PMID:15314165]

The intricate process of positive regulation of intrinsic apoptotic signaling pathway in response to DNA damage is a crucial cellular defense mechanism against genomic instability. Upon encountering DNA damage, the cell initiates a cascade of events designed to either repair the damage or, if irreparable, trigger programmed cell death (apoptosis) to prevent the propagation of mutated cells.

The initial step involves the detection of DNA damage by sensors like ATM (Ataxia Telangiectasia Mutated) and ATR (ATM and Rad3-related). These kinases are activated by DNA double-strand breaks and single-strand breaks, respectively. Activated ATM and ATR phosphorylate downstream effectors, including p53 and Chk1/Chk2, which are key players in the DNA damage response.

Phosphorylated p53, a transcription factor, induces the expression of pro-apoptotic proteins like Bax and Puma. These proteins translocate to the mitochondria, where they interact with anti-apoptotic proteins like Bcl-2 and Bcl-xL. The balance between pro- and anti-apoptotic proteins determines the fate of the cell.

If the damage is irreparable, Bax and Puma disrupt the mitochondrial membrane potential, leading to the release of cytochrome c into the cytoplasm. This release initiates the formation of the apoptosome, a complex consisting of cytochrome c, Apaf-1 (apoptotic protease activating factor-1), and caspase-9.

Caspase-9, a key executioner caspase, is activated within the apoptosome. Activated caspase-9 then activates downstream caspases, such as caspase-3, which trigger a cascade of events leading to cell death. These events include DNA fragmentation, nuclear condensation, and the formation of apoptotic bodies.

This intricate process of positive regulation ensures that the cell accurately senses and responds to DNA damage, either by initiating repair mechanisms or triggering apoptosis, ultimately safeguarding genomic integrity and preventing the propagation of harmful mutations.'
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Proteins (1)

Compounds (2)