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

Authors
Yim, HyungshinHwang, In SunChoi, Joon-SeokChun, Kwang-HoonJin, Ying HuaHam, Young-MiLee, Kwang YoulLee, Seung Ki
Issue Date
Jul-2006
Publisher
ROCKEFELLER UNIV PRESS
Citation
JOURNAL OF CELL BIOLOGY, v.174, no.1, pp.77 - 88
Indexed
SCIE
SCOPUS
Journal Title
JOURNAL OF CELL BIOLOGY
Volume
174
Number
1
Start Page
77
End Page
88
URI
https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/44753
DOI
10.1083/jcb.200509141
ISSN
0021-9525
Abstract
We show that caspase-3 cleaves Cdc6 at D-290/S and D-442/G sites, producing p32tCdc6 ( 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 etoposideinduced 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.
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