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Originally published In Press as doi:10.1074/jbc.M206109200 on July 29, 2002

J. Biol. Chem., Vol. 277, Issue 39, 36832-36838, September 27, 2002
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ATR Enforces the Topoisomerase II-dependent G2 Checkpoint through Inhibition of Plk1 Kinase*

Paula B. DemingDagger §, Kristina G. Flores§||, C. Stephen Downes**, Richard S. Paules||, and William K. KaufmannDagger Dagger Dagger

From the Dagger  Department of Pathology and Laboratory Medicine, Lineberger Comprehensive Cancer Center, and Center for Environmental Health and Susceptibility, University of North Carolina, Chapel Hill, North Carolina 27599, || Growth Control and Cancer Group, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709, and ** School of Biomedical Science, University of Ulster, Coleraine BT521SA, Northern Ireland

An ATR-dependent G2 checkpoint responds to inhibition of topoisomerase II and delays entry into mitosis by sustaining nuclear exclusion of cyclin B1-Cdk1 complexes. Here we report that induction of this checkpoint with ICRF-193, a topoisomerase II catalytic inhibitor that does not cause DNA damage, was associated with an ATR-dependent inhibition of polo-like kinase 1 (Plk1) kinase activity and a decrease in cyclin B1 phosphorylation. Expression of constitutively active Plk1 but not wild type Plk1 reversed ICRF-193-induced mitotic delay in HeLa cells, suggesting that Plk1 kinase activity is important for the checkpoint response to ICRF-193. G2/M synchronized normal human fibroblasts, when treated with ICRF-193, showed a decrease in cyclin B1 phosphorylation and Plk1 kinase activity despite high cyclin B1-Cdk1 kinase activity. G2 fibroblasts that were treated with caffeine to override the checkpoint response to ICRF-193 displayed a high incidence of chromosomal aberrations. Taken together, these results suggest that ATR-dependent inhibition of Plk1 kinase activity may be one mechanism to regulate cyclin B1 phosphorylation and sustain nuclear exclusion during the G2 checkpoint response to topoisomerase II inhibition. Moreover, the results demonstrate an important role for the topoisomerase II-dependent G2 checkpoint in the preservation of human genomic stability.

* This work was supported in part by Public Health Service Grants CA42765 (to W. K. K.), P30-CA16086, and P30-ES10126 and a grant from the Ulster Cancer Foundation (to C. S. D.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ These authors contributed equally to this work.

Supported by NIEHS, National Institutes of Health Environmental Pathology Training Grant T32-ES07017.

Dagger Dagger To whom correspondence should be addressed. Tel.: 919-966-8209; Fax: 919-966-9673; E-mail: bill_kaufmann@med.unc.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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