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The Involvement of Active DNA Synthesis in Camptothecin-induced G₂ Arrest: Altered Regulation of p34^cdc2/Cyclin B¹

Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Cell cycle arrest in G₂ phase is a common response to a variety of DNA-damaging agents. The coupling between DNA damage and G₂ arrest was studied in synchronized HeLa cells using camptothecin, a highly specific inhibitor of topoisomerase I that damages DNA through the formation of reversible topoisomerase I-DNA cleavable complexes. Brief camptothecin treatment of early S-phase HeLa cells caused arrest at G₂ phase and abolished the activation of p34^cdc2 protein kinase. Both tyrosine dephosphorylation of p34^cdc2 and cyclin B accumulation were altered. These cell cycle-dependent changes were not observed when DNA replication was inhibited by aphidicolin during the brief camptothecin treatment. Our results suggest that to produce G₂ arrest, active DNA synthesis is required at the time of camptothecin treatment, as was previously shown for camptothecin-induced cytotoxicity. Furthermore, our results suggest that the interaction of the replication fork with DNA damage may ultimately trigger altered regulation of p34^cdc2/cyclin B, leading to cell cycle arrest at the G₂ phase.

¹ This work was supported by NIH Grant CA39662 and the Burroughs Wellcome Fund.

² To whom requests for reprints should be addressed, at Department of Biological Chemistry, Johns Hopkins University, 725 N. Wolfe St., Baltimore, MD 21205.

Received 9/27/91. Accepted 1/24/92.

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