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Intra-S-Phase Checkpoint Activation by Direct CDK2 Inhibition

Molecular Oncology Laboratory,¹ Molecular Target Validation Laboratory,³ Cell Cycle Laboratory, Department of Discovery Research, DNAX Research, Inc., Palo Alto, California 94304,⁴ Department of Chemical Research, Schering-Plough Research Institute, Kenilworth, New Jersey 07033²

Received 13 January 2004/ Returned for modification 17 February 2004/ Accepted 29 April 2004

To ensure proper progression through a cell cycle, checkpoints have evolved to play a surveillance role in maintaining genomic integrity. In this study, we demonstrate that loss of CDK2 activity activates an intra-S-phase checkpoint. CDK2 inhibition triggers a p53-p21 response via ATM- and ATR-dependent p53 phosphorylation at serine 15. Phosphorylation of other ATM and ATR downstream substrates, such as H2AX, NBS1, CHK1, and CHK2 is also increased. We show that during S phase when CDK2 activity is inhibited, there is an unexpected loading of the minichromosome maintenance complex onto chromatin. In addition, there is an increased number of cells with more than 4N DNA content, detected in the absence of p53, suggesting that rereplication can occur as a result of CDK2 disruption. Our findings identify an important role for CDK2 in the maintenance of genomic stability, acting via an ATM- and ATR-dependent pathway.

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