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Published 17 July 2006. doi:10.1083/jcb.200604022
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 174, Number 2, 195-206
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Article

Condensin I recruitment and uneven chromatin condensation precede mitotic cell death in response to DNA damage



Michael Blank1, Yaniv Lerenthal1, Leonid Mittelman2, and Yosef Shiloh1

1 The David and Inez Myers Laboratory for Genetic Research, Department of Molecular Genetics and Biochemistry, and 2 Interdepartmental Core Facility, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel

Correspondence to Yosef Shiloh: yossih{at}post.tau.ac.il

Mitotic cell death (MCD) is a prominent but poorly defined form of death that stems from aberrant mitosis. One of the early steps in MCD is premature mitosis and uneven chromatin condensation (UCC). The mechanism underlying this phenomenon is currently unknown. In this study, we show that DNA damage in cells with a compromised p53-mediated G2/M checkpoint triggers the unscheduled activation of cyclin-dependent kinase 1 (Cdk1), activation and chromatin loading of the condensin I complex, and UCC followed by the appearance of multimicronucleated cells, which is evidence of MCD. We demonstrate that these processes engage some of the players of normal mitotic chromatin packaging but not those that drive the apoptotic chromatin condensation. Our findings establish a link between the induction of DNA damage and mitotic abnormalities (UCC) through the unscheduled activation of Cdk1 and recruitment of condensin I. These results demonstrate a clear distinction between the mechanisms that drive MCD-associated and apoptosis-related chromatin condensation and provide mechanistic insights and new readouts for a major cell death process in treated tumors.

Abbreviations used in this paper: ATM, ataxia telangiectasia mutated; Cdk1, cyclin-dependent kinase 1; DSB, double-strand break; hCAP, human chromatin-associated protein; IR, ionizing radiation; MCD, mitotic cell death; NCS, neocarzinostatin; PARP, poly(ADP-ribose)polymerase; PI, propidium iodide; shRNA, short hairpin RNA; SMC, structural maintenance of chromosomes; UCC, uneven chromatin condensation.


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