Chromosoma (2006) 115: 89–97 DOI 10.1007/s00412-005-0038-0 REVIEW Jay Z. Parrish . Ding Xue Cuts can kill: the roles of apoptotic nucleases in cell death and animal development Received: 25 October 2005 / Revised: 28 November 2005 / Accepted: 28 November 2005 / Published online: 18 January 2006 # Springer-Verlag 2006 Abstract Chromosome fragmentation is one of the major biochemical hallmarks of apoptosis. However, until recently, its roles in apoptosis and mechanisms of action remained elusive. Recent biochemical and genetic studies have shown that chromosome fragmentation is a complex biochemical process that involves a plethora of conserved nucleases with distinct nuclease activities and substrate specificities. These apoptotic nucleases act cooperatively among themselves and with other nonnuclease cofactors to promote stepwise chro- mosome fragmentation and DNA degradation. Importantly, in addition to its direct contribution to the dismantling of the dying cell, apoptotic DNA degradation can facilitate cell killing and other apoptotic events such as clearance of apoptotic cells. Furthermore, some apoptotic nucleases ap- parently affect other aspects of animal development, includ- ing immune responses. The identification of new apoptotic nucleases and analysis of their functions in apoptosis and animal development should pave the way for future studies to uncover new functions for apoptotic nucleases and shed light on the hidden links between apoptotic DNA degrada- tion and human diseases. Introduction Programmed cell death, or apoptosis, is a highly regulated process necessary for the proper sculpting of structures during development, maintenance of appropriate cell num- ber, and the elimination of unnecessary or damaged cells (Kerr et al. 1972; Danial and Korsmeyer 2004). Improper regulation of programmed cell death can lead to a variety of diseased states, including cellular transformations and degenerative disorders (Thompson 1995). Cells undergoing apoptosis display similar morphological changes in mam- mals and invertebrates, including Drosophila melanogaster and Caenorhabditis elegans (C. elegans), suggesting that evolutionarily conserved machineries may be employed to execute these characteristic changes in dying cells. One of the hallmarks of apoptosis is the fragmentation of chromosomal DNA (Wyllie 1980). In dying cells, chromo- somes condense and are cleaved at internucleosomal regions to generate approximately 180-bp DNA ladders, irreversibly compromising the ability of a cell to replicate its genome and to transcribe its genes, which are important for cell survival. This represents one of the most severe assaults levied against a dying cell and likely contributes directly to the demise of the cell. Despite the importance of this event, how it is ac- tivated and executed during apoptosis and whether it is a cause or simply a secondary event of apoptosis were, until recently, poorly understood. Furthermore, a variety of differ- ent nucleases have been implicated in apoptotic DNA deg- radation, but only recently were the identities of some of these nucleases revealed and their roles in apoptosis con- firmed in vivo. A number of excellent reviews have focused on the discovery and mechanisms of action of some of these apoptotic nucleases (Nagata 2000; Zhang and Xu 2002; Samejima and Earnshaw 2005; Widlak and Garrard 2005). However, an equally important issue has received less attention, that is, what are the developmental consequences of disrupting apoptotic DNA degradation in vivo? In an attempt to address the roles of DNA degradation in apoptosis and normal animal development, we will review the findings from genetic studies of animals defective in apoptotic DNA Communicated by E.A. Nigg J. Z. Parrish . D. Xue (*) Department of Molecular, Cellular and Developmental Biology, University of Colorado, Boulder, CO 80309, USA e-mail: ding.xue@colorado.edu Tel.: +1-303-4920271 Fax: +1-303-4927744 J. Z. Parrish Howard Hughes Medical Institute, Departments of Physiology and Biochemistry, University of California San Francisco, Room GD481, 1550 4th St., Rock Hall, San Francisco, CA 94143, USA