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DNA Damage-Induced Apoptosis Oncogene (2004) 23, 2797–2808 & 2004 Nature Publishing Group All rights reserved 0950-9232/04 $25.00 www.nature.com/onc DNA damage-induced apoptosis Chris J Norbury1 and Boris Zhivotovsky*,2 1Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK; 2Institute of Environmental Medicine, Karolinska Institutet, Box 210, Nobels va¨g. 13, SE-171 77 Stockholm, Sweden Unicellular organisms respond to the presence of DNA phila melanogaster.The combination of data from these lesions by activating cell cycle checkpoint and repair genetically amenable models with those from mamma- mechanisms, while multicellular animals have acquired the lian and other vertebrate species has revealed conserva- further option of eliminating damaged cells by triggering tion of several key molecular mechanisms, as well as apoptosis. Defects in DNA damage-induced apoptosis species-specific variations on these themes. contribute to tumorigenesis and to the resistance of cancer Most of the morphological criteria that were first used cells to a variety of therapeutic agents. The intranuclear to distinguish apoptosis from necrosis relate to the mechanisms that signal apoptosis after DNA damage nucleus (Kerr et al., 1972). Degradation of chromoso- overlap with those that initiate cell cycle arrest and DNA mal DNA into oligonucleosome length fragments in repair, and the early events in these pathways are highly irradiated lymphoid tissues was reported as early as conserved. In addition, multiple independent routes have 1976 (Skalka et al., 1976). This observation was first recently been traced by which nuclear DNA damage can linked to endonuclease activation in 1980 (Wyllie, 1980) be signalled to the mitochondria, tipping the balance in and has since been used as a biochemical marker of favour of cell death rather than repair and survival. Here, apoptosis.Transcriptional activation of gene expression we review current knowledge of nuclear DNA damage is also a common, though not universal, feature of signalling, giving particular attention to interactions apoptosis.Unsurprisingly, the interest of many re- between these nuclear events and apoptotic processes in searchers in the field was therefore initially focused on other intracellular compartments. understanding the nuclear involvement in apoptosis Oncogene (2004) 23, 2797–2808. doi:10.1038/sj.onc.1207532 signalling.Questions about the primacy of nuclear events were raised when NUC-1, a protein essential Keywords: DNA damage; DNA repair; apoptosis; for apoptotic DNA degradation in C. elegans, was mechanisms shown to act downstream of the key apoptotic regulators CED-3 and CED-4 (Ellis and Horvitz, 1986).In some cases, DNA degradation required prior engulfment of apoptotic cells by phagocytes, again indicating that nuclease activation is a late event. Introduction In addition, upon treatment with staurosporine or antibodies against Fas (Apo-1/CD95), enucleate The integrity of genomic DNA is constantly under cells (cytoplasts) underwent morphological changes threat, even in perfectly healthy cells.DNA damage can characteristic of apoptosis, which could be inhibited result from the action of endogenous reactive oxygen by overexpression of the antiapoptotic protein species, or from stochastic errors in replication or Bcl-2 (Jacobson et al., 1994; Schulze-Osthoff et al., recombination, as well as from environmental and 1994). therapeutic genotoxins.While unicellular organisms A variety of strands of evidence subsequently respond to the presence of DNA lesions by activating indicated that caspases (cysteine-aspartate proteases) cell cycle checkpoint and repair mechanisms, multi- play central roles in apoptotic signalling and execution cellular animals have the additional possibility of (Thornberry, 1999 and references therein).The shift of eliminating the damaged cells by triggering their death. focus from the nucleus to the cytoplasm became even Induction of apoptosis has been recognized as a possible more pronounced when, in the mid-1990s, Wang and outcome of DNA damage for more than 20 years co-workers demonstrated that the release of cytochrome (Wyllie et al., 1980). The earlier literature in this area is c from mitochondria into the cytosol resulted in caspase dominated by studies of mammalian systems, but it has activation and the execution of apoptosis (Liu et al., since become apparent that DNA damage can also 1996).This, along with related key observations, led to induce apoptosis in diverse experimental model organ- an explosion in research focusing on mitochondrial isms, most notably Caenorhabditis elegans and Droso- regulation of apoptosis (for a review, see Cory and Adams, 2002).It is clear that any coherent view of the *Correspondence: B Zhivotovsky; apoptotic response to DNA damage must take into E-mail: [email protected] account events in the nucleus and the cytoplasm, as well DNA damage and apoptosis CJ Norbury and B Zhivotovsky 2798 as the regulatory traffic within and between these compartments. Sensitivity and resistance to DNA damage-induced apoptosis Animal cells differ markedly in their propensity to commit to apoptotic death following DNA damage. Thymocytes, for example, are exquisitely primed to engage apoptosis in response to DNA damage as well as a variety of other triggers.By contrast, primary fibroblasts appear to undergo DNA damage-induced apoptosis (DDIA) rarely, if at all – a feature of these cells familiar to anyone who has irradiated them for use as ‘feeder’ layers in cell culture systems.These differing apoptotic thresholds presumably reflect differing basal patterns of expression of pro- and anti-apoptotic regulators, and generally relate to the importance of Figure 1 Life versus death decisions following DNA damage. apoptosis during the normal developmental programme Common damage detection and signal transduction mechanisms of the cells in question.The relative radiosensitivity of are shared between pathways governing DNA repair, cell cycle thymocytes, for instance, can be related to their checkpoint activation and apoptosis.The consequence of any given propensity for apoptosis during negative selection in level of DNA damage is cell type-specific.By allowing the survival and proliferation of cells with damaged DNA, failure of these vivo.Cells less prone to triggering apoptosis can use processes contributes to tumorigenesis and resistance to cancer alternative strategies to avoid the propagation of therapies mutations that might otherwise threaten the health of the whole organism. (Di Leonardo et al., 1994; Baus et al., 2003). In this way, the threat posed by proliferation of mutated cells is Consequences of cell survival after DNA damage effectively eliminated without recourse to apoptosis.On the other hand, it is important that the apoptotic Loss of apoptosis undoubtedly plays a major role in programme, once initiated, is completed (Figure 1). tumorigenesis (Igney and Krammer, 2002).Studies in Transient activation of the caspase-activated DNase this area have frequently addressed the significance of (CAD) followed by cell recovery might even contribute loss of p53-dependent apoptosis in response to oncogene to the initiation of site-specific chromosomal transloca- activation or hypoxia, but loss of DDIA probably also tions during tumorigenesis (Vaughan et al., 2002). contributes significantly to tumour development.The Perhaps for this reason amplification mechanisms, issue is complicated by the fact that many of the notably those involving release of mitochondrial pro- mediators of DDIA have additional functions in cell teins following permeabilization of the outer mitochon- cycle regulation and/or DNA repair, which in turn can drial membrane, drive the complete destruction of the have dramatic influences on genome stability.For cell following commitment to DDIA, as discussed example, loss of function of the XPB or XPD helicase, below. as seen in xeroderma pigmentosum patients, results in Loss of apoptotic potential probably also makes a defective DDIA as well as defective nucleotide excision significant contribution to the resistance of cancer cells repair and a hugely elevated frequency of UV-induced to therapies that induce DNA damage (Lowe et al., skin tumours (Wang et al., 1996). Similarly, the ATM 1993a).It would be a gross oversimplification to protein kinase is required for a variety of cell cycle consider cancer cells simply as apoptosis-defective checkpoint responses to DNA double-strand breaks versions of their normal counterparts.There is no (DSB), but roles for this protein in DNA repair and doubt, however, that loss of function of proapoptotic DDIA have also been identified, as discussed below.It is regulators such as p53 and/or overexpression of anti- therefore difficult to determine the extent to which the apoptotic proteins such as Bcl-2 can tilt the balance in excess tumour incidence seen in ataxia telangiectasia favour of tumour cell survival following DNA damage- (AT) (ATMÀ/À) patients is attributable specifically to based therapy. apoptotic defects. Even in the absence of faithful DNA repair, cell survival following DNA damage is not necessarily Signals linking DNA damage to cell cycle arrest, DNA associated with an increased risk of tumorigenesis.The repair or apoptosis lack of DDIA in primary fibroblasts, for example, is balanced by the capacity of these cells to maintain Any signalling pathway responding to DNA damage long-term p53-dependent cell cycle arrest in G1 or G2 must comprise one or more sensors, coupled via
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