apoptotic DNA fragmentation

Definition

Target type: biologicalprocess

The cleavage of DNA during apoptosis, which usually occurs in two stages: cleavage into fragments of about 50 kbp followed by cleavage between nucleosomes to yield 200 bp fragments. [GOC:dph, GOC:mah, GOC:mtg_apoptosis, GOC:tb, ISBN:0721639976, PMID:15723341, PMID:23379520]

Apoptotic DNA fragmentation is a critical and tightly regulated process that occurs during programmed cell death, or apoptosis. It involves the cleavage of genomic DNA into specific, ladder-like fragments of approximately 180 base pairs and multiples thereof. This characteristic fragmentation pattern is a hallmark of apoptosis and can be visualized using gel electrophoresis.

The process of apoptotic DNA fragmentation is initiated by the activation of a family of cysteine proteases known as caspases. Caspases are key executioners of apoptosis, and their activation leads to a cascade of events that ultimately result in cell death. One of the major caspase targets is a nuclear enzyme called **CAD** (caspase-activated DNase).

**CAD**, also known as DFF40, is a nuclease that remains inactive in healthy cells due to its association with an inhibitory protein, ICAD (inhibitor of caspase-activated DNase). During apoptosis, activated caspases cleave ICAD, releasing active CAD into the nucleus.

Once in the nucleus, **CAD** begins the process of DNA fragmentation. It cleaves the DNA at specific sites, typically within the linker regions between nucleosomes. The resulting DNA fragments are often referred to as "ladder fragments" because they form a distinct ladder pattern when separated by electrophoresis.

**Mechanisms of Apoptotic DNA Fragmentation:**

* **Cleavage of linker DNA:** **CAD** preferentially cleaves the linker DNA between nucleosomes, leaving the nucleosomal DNA intact. This results in the characteristic ladder pattern of DNA fragments.
* **Activation of other nucleases:** Caspases can also activate other nucleases involved in DNA fragmentation, including **endonucleases G** and **DNase I**.
* **Chromatin condensation:** Apoptotic DNA fragmentation is often accompanied by chromatin condensation, which brings the DNA into closer proximity to the nucleases, facilitating their activity.

**Significance of Apoptotic DNA Fragmentation:**

* **Elimination of damaged or unwanted cells:** Apoptotic DNA fragmentation helps to ensure the orderly removal of cells that are damaged, infected, or no longer needed.
* **Prevention of inflammation:** The controlled degradation of DNA during apoptosis helps to prevent the release of potentially harmful cellular contents and inflammatory signals.
* **Development and tissue homeostasis:** Apoptotic DNA fragmentation plays a crucial role in development, tissue homeostasis, and the immune response.

**Regulation of Apoptotic DNA Fragmentation:**

* **Caspase activation:** The activation of caspases is a critical step in the initiation of apoptotic DNA fragmentation.
* **Inhibition of CAD:** The activity of CAD is tightly regulated by its interaction with ICAD, ensuring that DNA fragmentation occurs only during apoptosis.
* **Other regulatory proteins:** Several other proteins play a role in the regulation of apoptotic DNA fragmentation, including **DNA repair enzymes**, **anti-apoptotic proteins**, and **transcription factors**.'"

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