The caspase‐activated DNase: apoptosis and beyond

• Published in: The FEBS journal Vol. 284; no. 8; pp. 1160 - 1170
• Main Authors: Larsen, Brian D., Sørensen, Claus S.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-04-2017
• Subjects: Animals; Apoptosis; CAD; Caspase; Caspases - metabolism; Cell death; Cell differentiation; Cell fate; cell fate control; Cell Lineage; Cell proliferation; Deactivation; Deoxyribonuclease; Deoxyribonucleases - metabolism; Deoxyribonucleic acid; Differentiation (biology); DNA; DNA breaks; DNA Damage; DNA Repair; Genes; Humans; ICAD; Inactivation; Mortality; Mutation; Neoplasms - enzymology; Neoplasms - genetics; Neoplasms - pathology; p53 Protein; Senescence; Signal transduction; apoptosis; cell fate control; DNA breaks; CAD; ICAD; caspase
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.13970

Organismal development and function requires multiple and accurate signal transduction pathways to ensure that proper balance between cell proliferation, differentiation, inactivation, and death is achieved. Cell death via apoptotic caspase signal transduction is extensively characterized and integral to this balance. Importantly, the view of apoptotic signal transduction has expanded over the previous decades. Subapoptotic caspase signaling has surfaced as mechanism that can promote the adoption of a range of cellular fates. An emerging mechanism of subapoptotic caspase signaling is the activation of the caspase‐activated DNase (CAD) through controlled cleavage of the inhibitor of CAD (ICAD). CAD‐induced DNA breaks incite a DNA damage response, frequently invoking p53 signaling, that transduces a change in cell fate. Cell differentiation and senescence are fates demonstrated to arise from CAD‐induced DNA breaks. Furthermore, an apparent consequence of CAD activity is also emerging, as a potential source of oncogenic mutations. This review will discuss the mechanisms underlying CAD‐induced DNA breaks and highlight how CAD activity promotes diverse cell fates.
The caspase‐activated DNase (CAD) is a driver of apoptotic DNA fragmentation, but developing observations have implicated the activity of the nuclease in the adoption of nonapoptotic cellular fates. Nonapoptotic cell fate outcomes arising from CAD‐induced DNA breaks included differentiation, senescence, and transformation. This review will discuss the mechanisms underlying CAD‐induced DNA breaks and highlight how CAD activity promotes diverse cell fates.