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Published online 26 June 2006. doi:10.1083/jcb.200509141
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 174, Number 1, 77-88
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Article

 Cleavage of Cdc6 by caspase-3 promotes ATM/ATR kinase–mediated apoptosis of HeLa cells

Hyungshin Yim1, In Sun Hwang1, Joon-Seok Choi1, Kwang-Hoon Chun1, Ying Hua Jin2, Young-Mi Ham1, Kwang Youl Lee3, and Seung Ki Lee1

1 Division of Pharmaceutical Biosciences, Research Institute for Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 151-742, Korea
2 College of Life Science, Jilin University, Changchun 130012, China
3 College of Pharmacy, Chonnam National University, Gwangju 500-757, Korea

Correspondence to Seung Ki Lee: sklcrs{at}plaza.snu.ac.kr

We show that caspase-3 cleaves Cdc6 at D290/S and D442/G sites, producing p32-tCdc6 (truncated Cdc6) and p49-tCdc6, respectively, during etoposide- or tumor necrosis factor (TNF)-{alpha}–induced apoptosis. The expression of these tCdc6 proteins, p32- and p49-tCdc6, promotes etoposide-induced apoptosis. The expression of tCdc6 perturbs the loading of Mcm2 but not Orc2 onto chromatin and activates ataxia telangiectasia mutated (ATM) and ATM and Rad-3 related (ATR) kinase activities with kinetics similar to that of the phosphorylation of Chk1/2. The activation kinetics are consistent with elevated cellular levels of p53 and mitochondrial levels of Bax. The tCdc6-induced effects are all suppressed to control levels by expressing a Cdc6 mutant that cannot be cleaved by caspase-3 (Cdc6-UM). Cdc6-UM expression attenuates the TNF-{alpha}–induced activation of ATM and caspase-3 activities. When ATM or ATR is down-expressed by using the small interfering RNA technique, the TNF-{alpha}– or tCdc6-induced activation of caspase-3 activities is suppressed in the cells. These results suggest that tCdc6 proteins act as dominant-negative inhibitors of replication initiation and that they disrupt chromatin structure and/or induce DNA damage, leading to the activation of ATM/ATR kinase activation and p53–Bax-mediated apoptosis.

Abbreviations used in this paper: ATM, ataxia telangiectasia mutated; ATR, ATM and Rad-3 related; NES, nuclear export signal; ORC, origin RC; PARP, poly (ADP-ribose) polymerase; PI, propidium iodide; RC, replicative complex; tCdc6, truncated Cdc6; wt, wild type.


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