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Published online 29 November 2004. doi:10.1083/jcb.200404105
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 167, Number 5, 851-862
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Article

Contrasting nuclear dynamics of the caspase-activated DNase (CAD) in dividing and apoptotic cells



Delphine Lechardeur1, Ming Xu2, and Gergely L. Lukacs1

1 Program in Cell and Lung Biology, Hospital for Sick Children Research Institute and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 1X8, Canada
2 Department of Cell Biology, Neurobiology, and Anatomy, University of Cincinnati College of Medicine, Cincinnati, OH 45267

Correspondence to G.L. Lukacs: glukacs{at}sickkids.ca

Although compelling evidence supports the central role of caspase-activated DNase (CAD) in oligonucleosomal DNA fragmentation in apoptotic nuclei, the regulation of CAD activity remains elusive in vivo. We used fluorescence photobleaching and biochemical techniques to investigate the molecular dynamics of CAD. The CAD-GFP fusion protein complexed with its inhibitor (ICAD) was as mobile as nuclear GFP in the nucleosol of dividing cells. Upon induction of caspase-3–dependent apoptosis, activated CAD underwent progressive immobilization, paralleled by its attenuated extractability from the nucleus. CAD immobilization was mediated by its NH2 terminus independently of its DNA-binding activity and correlated with its association to the interchromosomal space. Preventing the nuclear attachment of CAD provoked its extracellular release from apoptotic cells. We propose a novel paradigm for the regulation of CAD in the nucleus, involving unrestricted accessibility of chromosomal DNA at the initial phase of apoptosis, followed by its nuclear immobilization that may prevent the release of the active nuclease into the extracellular environment.

Abbreviations used in this paper: CAD, caspase-activated DNase; CIDE, cell-inducing DFF45-like effector; DFF, DNA fragmentation factor; FLIP, fluorescence loss induced by photobleaching; HMG, high mobility group; ICAD, inhibitor of caspase-activated DNase; MEF, mouse embryonic fibroblast; NuMA, nuclear mitotic apparatus protein; STS, staurosporine.


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