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Adaptation to the Ionizing Radiation–Induced G₂ Checkpoint Occurs in Human Cells and Depends on Checkpoint Kinase 1 and Polo-like Kinase 1 Kinases

Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Copenhagen, Denmark

Requests for reprints: Randi G. Syljuåsen, Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Strandboulevarden 49, 2100 Copenhagen, Denmark. Phone: 45-35257334; Fax: 45-35257721; E-mail: rs{at}cancer.dk.

Checkpoint adaptation was originally defined in yeast as the ability to divide despite the presence of damaged DNA. An important unanswered question is whether checkpoint adaptation also occurs in human cells. Here, we show that following the ionizing radiation–induced G₂ checkpoint, human osteosarcoma cells entered mitosis with -H2AX foci, a marker for unrepaired DNA double-strand breaks. Exit from the G₂ checkpoint was accelerated by inhibiting the checkpoint kinase 1 (Chk1) and delayed by overexpressing wild-type Chk1 or depleting the Polo-like kinase 1 (Plk1). Chk1 and Plk1 controlled this process, at least partly, via independent signaling pathways. Our results suggest that human cells are able to exit the checkpoint arrest and divide before the damage has been fully repaired. Such cell division in the presence of damaged DNA may be detrimental for genetic stability and could potentially contribute to cancer development. (Cancer Res 2006; 66(21): 10253-7)

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