Caspase-3 activation is a critical event in apoptosis. Which of the following correctly describes the role of caspase-3 in the apoptotic pathway?

## Caspase-3: The Executioner of Apoptosis **Key Point:** Caspase-3 is the **executioner caspase** — the final common effector in both intrinsic and extrinsic apoptotic pathways. Its activation triggers the morphological and biochemical hallmarks of apoptosis. ### Apoptotic Caspase Cascade ```mermaid flowchart TD A[Apoptotic stimulus]:::outcome --> B{Extrinsic or Intrinsic?}:::decision B -->|Extrinsic| C[Death receptor activation]:::action B -->|Intrinsic| D[Mitochondrial stress]:::action C --> E[Caspase-8 activation]:::action D --> F[Cytochrome c release]:::action F --> G[Apoptosome formation]:::action G --> H[Caspase-9 activation]:::action E --> I[Caspase-3 activation]:::urgent H --> I I --> J[PARP cleavage]:::action I --> K[CAD/DFF45 cleavage]:::action I --> L[DNA fragmentation]:::outcome I --> M[Apoptotic body formation]:::outcome ``` ### Substrates Cleaved by Caspase-3 | Substrate | Function | Result of Cleavage | |-----------|----------|--------------------| | **PARP** (Poly-ADP-ribose polymerase) | DNA repair enzyme | Loss of DNA repair capacity; 89 kDa → 85 kDa fragment | | **CAD/DFF45** (Caspase-Activated DNase) | Endonuclease | Release of CAD; nuclear translocation and internucleosomal DNA cleavage | | **Lamin A/C** | Nuclear scaffold protein | Nuclear envelope breakdown; chromatin condensation | | **Actin** | Cytoskeletal protein | Cell rounding and membrane blebbing | **High-Yield:** Caspase-3 cleavage of **PARP** is a widely used **biochemical marker of apoptosis** in laboratory and clinical settings. Detection of 85 kDa PARP fragment confirms active apoptosis. ### Initiator vs Executioner Caspases | Caspase | Type | Pathway | Function | |---------|------|---------|----------| | **Caspase-8** | Initiator | Extrinsic | Activated by DISC; cleaves caspase-3 | | **Caspase-9** | Initiator | Intrinsic | Activated by apoptosome; cleaves caspase-3 | | **Caspase-3** | **Executioner** | **Both** | **Cleaves PARP, CAD, lamins; executes apoptosis** | | **Caspase-7** | Executioner | Both | Redundant with caspase-3; lesser role | **Clinical Pearl:** In cancer therapy, many drugs (e.g., chemotherapy, targeted therapies) work by triggering apoptosis through caspase-3 activation. Tumors that evade caspase-3 activation develop chemotherapy resistance. **Mnemonic:** **CAD** = **C**aspase-**A**ctivated **D**NAse. When caspase-3 cuts CAD loose, DNA gets cut into pieces.