Apoptotic DNA fragmentation and tissue homeostasis

Apoptotic cell death can be triggered by many different cellular stimuli, resulting in activation of apoptotic signaling pathways including caspases (see Caspase Cascade pathway) and mitochondria (see Role of Mitochondria in Apoptotic Signaling pathway). A cellular response that is characteristic of apoptosis is fragmentation of the nuclear genome to create a nucleosomal ladder. This activity is conducted by multiple nucleases activated by apoptotic signaling pathways. One nuclease involved in apoptosis is DNA fragmentation factor (DFF), a caspase-activated DNAse (CAD). DFF/CAD is activated through cleavage of its associated inhibitor ICAD by caspases proteases during apoptosis. DFF/CAD interacts with chromatin components such as topo II and histone H1 to condense chromatin structure and perhaps recruit CAD to chromatin. Another apoptosis activated protease is endonuclease G, EndoG. EndoG is encoded in the nuclear genome but is localized to mitochondria in normal cells. EndoG may play a role in the replication of the mitochondrial genome, as well as in apoptosis. Apoptotic signaling causes the release of EndoG from mitochondria. Mitochondria are involved in apoptotic signaling in other ways as well, through the release of cytochrome c induced by Bid to activate the caspase protease cascade. These pathways are independent since the EndoG pathway still occurs in cells lacking DFF.

Contributor: Glenn Croston Ph.D.

REFERENCES: Durrieu F, Samejima K, Fortune J, Kandels-Lewis S, Osheroff N, Earnshaw W. DNA topoisomerase IIa interacts with CAD nuclease and is involved in chromatin condensation during apoptotic execution. Current Biology, vol 10, July 2000, 923-26. Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S. A caspase-activated Dnase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature, vol 391, January 1998, 43-50. Hengartner, M.O. Apoptosis. DNA destroyers. Nature, vol 412(6842). 2001. 27, 29 Li, L.Y., Luo, X., Wang, X.. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature, vol 412(6842), 2001, 95-99. Liu, X., et al. Activation of the apoptotic endonuclease DFF40 (caspase-activated Dnase or nuclease). Oligomerization and direct interaction with histone H1. Biochem. J., vol 274(20), 1999, 13836-40. Tang, D., Kidd, V.J. Cleavage of DFF-45/ICAD by multiple caspases is essential for its function during apoptosis. Biochem. J., Vol 273(44), 1998, 28549-52. Zhang, Jianhua, and Ming Xu. Apoptotic DNA fragmentation and tissue homeostasis. TRENDS in Cell Biology, vol 12(2), February 2002, 84-89.