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Papers In Press, published online ahead of print July 29, 2002
Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599
Corresponding Author: bill_kaufmann{at}med.unc.edu
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 Plk1 kinase activity and a decrease in cyclin B1phosphorylation. 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 to 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.
J. Biol. Chem, 10.1074/jbc.M206109200
Submitted on June 19, 2002
Revised on July 19, 2002
Accepted on July 29, 2002
ATR enforces the topoisomerase II-dependent G2 checkpoint through inhibition of Plk1 kinase
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