intrinsic apoptotic signaling pathway in response to DNA damage

Definition

Target type: biologicalprocess

The series of molecular signals in which an intracellular signal is conveyed to trigger the apoptotic death of a cell. The pathway is induced by the detection of DNA damage, and ends when the execution phase of apoptosis is triggered. [GOC:go_curators, GOC:mtg_apoptosis]

The intrinsic apoptotic signaling pathway, also known as the mitochondrial pathway, is a crucial mechanism that eliminates cells with irreparable DNA damage to maintain genomic integrity and prevent uncontrolled cell proliferation. This process is triggered by a variety of stimuli, including DNA double-strand breaks (DSBs), which are particularly dangerous lesions that can lead to mutations or chromosome rearrangements.

Upon sensing DNA damage, the cell activates a cascade of signaling events that ultimately culminate in the release of pro-apoptotic proteins from the mitochondria into the cytoplasm. These proteins, including cytochrome c, Smac/DIABLO, and AIF, then initiate a proteolytic cascade that activates caspase enzymes, ultimately leading to cell death.

Here's a detailed breakdown of the key steps involved in the intrinsic apoptotic signaling pathway in response to DNA damage:

1. **DNA Damage Sensing and Signal Transduction:**
* **ATM Activation:** The primary sensor of DNA damage, particularly DSBs, is the ataxia telangiectasia mutated (ATM) protein kinase. ATM is activated by DNA damage and phosphorylates numerous downstream substrates, including p53, CHK2, and BRCA1, triggering DNA repair mechanisms and cell cycle checkpoints.
* **p53 Activation:** The tumor suppressor protein p53 is a crucial player in the apoptotic response. p53 is activated by ATM phosphorylation and other signaling pathways. Upon activation, p53 can induce cell cycle arrest to allow for DNA repair, or it can directly trigger apoptosis if the damage is too severe.
* **Other Signaling Pathways:** Other signaling molecules, such as the p38 MAPK and JNK pathways, can also contribute to the intrinsic apoptotic pathway by activating transcription factors that induce pro-apoptotic genes.

2. **Mitochondrial Membrane Permeabilization:**
* **Bcl-2 Family Proteins:** The Bcl-2 family of proteins is a critical regulator of mitochondrial outer membrane permeabilization (MOMP), a key event in intrinsic apoptosis. This family consists of both pro-apoptotic (e.g., Bax, Bak) and anti-apoptotic (e.g., Bcl-2, Bcl-xL) members.
* **Bax/Bak Activation:** In response to DNA damage signals, pro-apoptotic Bcl-2 proteins, Bax and Bak, are activated. They oligomerize and insert into the mitochondrial outer membrane, forming pores that allow the release of pro-apoptotic molecules.
* **BH3-Only Proteins:** BH3-only proteins (e.g., Bim, Bid, Puma) are activated by various apoptotic stimuli, including DNA damage, and act as sensors of stress. They bind and inhibit anti-apoptotic Bcl-2 proteins, allowing Bax/Bak to activate MOMP.

3. **Release of Apoptotic Factors:**
* **Cytochrome c:** The most important pro-apoptotic factor released from the mitochondria is cytochrome c, a component of the electron transport chain. Once in the cytoplasm, cytochrome c binds to Apaf-1, activating caspase-9.
* **Smac/DIABLO and Omi/HtrA2:** These proteins inhibit IAPs (inhibitors of apoptosis proteins), which normally block the activity of caspases.
* **AIF (Apoptosis-inducing factor):** AIF is a caspase-independent apoptosis inducer that translocates to the nucleus, leading to DNA fragmentation and chromatin condensation.

4. **Caspase Cascade Activation and Cell Death Execution:**
* **Caspase-9 Activation:** Cytochrome c, Apaf-1, and caspase-9 form the apoptosome, a multiprotein complex that activates caspase-9, the initiator caspase of the intrinsic pathway.
* **Caspase Cascade:** Active caspase-9 activates downstream effector caspases, such as caspase-3 and caspase-7, which cleave and activate other proteins, ultimately leading to cell death.
* **Apoptosis Execution:** Caspase activation leads to a series of morphological and biochemical changes characteristic of apoptosis, including DNA fragmentation, nuclear condensation, and formation of apoptotic bodies.

The intrinsic apoptotic signaling pathway is a tightly regulated process that plays a vital role in maintaining cellular homeostasis and preventing the accumulation of damaged cells. Defects in this pathway can contribute to cancer development, neurodegenerative diseases, and other pathological conditions.'
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Proteins (24)

Compounds (528)