Calcium endonucleases

Sustained cytosolic Ca2+ overload usually results in a different route leading to cell death. It mainly relies on the activation of the calcium/calmodulin (CaM)-dependent phosphatase, calcineurin. Calcineurin-catalyzed dephosphorylation promotes apoptosis by regulating the activity of a number of downstream targets, including the pro-apoptotic Bcl-2 family member, Bad (Wang, et al., 1999), and transcription factors of the NFAT (nuclear factor of activated T cells) family (Rao, et al., 1997). There are also other Ca2+-dependent enzymes contributing to the apoptotic events, and they include several DNA-degrading endonucleases (Robertson, et al., 2000) and Ca2+-activated cystein proteases of the calpain family essential for the enzymatic activation of the crucial pro-apoptotic effectors (Altznauer, et al., 2004). 

Overactivation of the NMDA subtype of glutamate receptors results in excessive Ca2+ influx via the receptor-associated cation channel leading to the activation of calcium-dependent enzymes, such as proteases, endonucleases, and nitric oxide synthases (NOSs) and to the production of nitrogen as well as oxygen free radicals thus contributing to cell death (Choi, 1990 Lipton, 2006 Lipton and Nicotera, 1998 Lynch and Guttmann, 2002). 

ATPases, phospholipases, proteases, and endonucleases. Thus increased calcium causes increased mitochondrial permeability and induction of apoptosis and necrosis. Calcium is required for maintenance and function of the cytoskeleton as well (Delgado-Coello et al, 2006 Dahm and Jones, 1996). 

Cohen, J. J. and Duke, R. C. (1984) Glucocorticoid activation of a calcium dependent endonuclease in thymocyte nuclei leads to cell death. J. Immunol. 132,38 42. 

As ATP levels decrease, cellular calcium levels increase and activate a number of proteases, endonucleases, and other enzymes. Caspase enzymes also become activated. Caspase-3 rapidly cleaves PARP not bound to DNA, and to a lesser extent DNA-bound PARP. When PARP is cleaved, DNA is vulnerable to the actions of endonuclease, which is part of the apoptotic program. 

Gaido, M.L. and Cidlowski, J.A. (1991) Identification, purification and characterization of a calcium-dependent endonuclease (NUC18) from apoptotic rat thymocytes. NUC18 is not histone H2B. J. Biol. Chem. 266 18580-18585. 

The role of the divalent metal ions present in natural phosphodiesterases became clear in bovine pancreatic deoxyribonuclease I (DNase I), the first endonuclease structure determined by X-ray crystallography. The nucleophilic attack of a water molecule activated by a histidine residue is facilitated by the interaction of a calcium ion with the phosphate group to be cleaved (291). Glutamic and aspartic residues involved in magnesium binding have been identified in the crystal structure of four type II restriction enzymes EcoRl (292), EcoRV (293), Pvull (294), and BamHl (295), as well as in that of the repair... 

Corcoran GB, Wong BK, Neese BL (1987) Early sustained rise in total liver calcium during acetaminophen hepatotoxicity in mice. Res Commun Chem Pathol Pharmacol 58 291-305 Cover C, Mansouri A, Knight TR, Bajt ML, Lemasters JJ, Pessayre D, Jaeschke H (2005) Peroxynitrite-induced mitochondrial and endonuclease-mediated nuclear DNA damage in acetaminophen hepatotoxicity. J Pharmacol Exp Ther 315 879-887 Cover C, Liu J, Farhood A, Malle E, Waalkes MP, Bajt ML, Jaeschke H (2006) Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity. Toxicol Appl Pharmacol 216 98-107... 

The cytostatic activities of the cholestane glycosides partly resulted from the induction of apoptosis. The apoptosis is caused by the activation of calcium dependent endonuclease. An analysis of flow cytometry pointed out that glycosides stopped the cell cycle of HL-60 at S2/M phase and induced apoptosis at GO/Gl phase . 

Numerous enzyme systems are impacted by NMDA receptor-mediated intracellular calcium increase. Caspases, a family of endonucleases, trigger excitotoxicity-induced apoptosis Zipfel et al., 20(X)). Another family of proteases, the calpains, degrades the cytoskeleton, receptors, G proteins, and calcium binding proteins when activated (Emerich, 1999). 

Hewish DR, Burgoyne LA (1973) The calcium dependent endonuclease activity of isolated nuclear preparations. Relationship between its occurence and the occurence of other classes of enzymes found in nuclear preparations. Biochem Biophys Res Commun 52 475-781... 

---