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MBC in Press, published online ahead of print October 17, 2007
Mol. Biol. Cell 10.1091/mbc.E07-06-0525

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Submitted on June 4, 2007
Revised on October 2, 2007
Accepted on October 10, 2007

p21 Inhibits Cdk1 in the Absence of Cdk2 to Maintain the G1/S Phase DNA Damage Checkpoint

Ande Satyanarayana, Mary Beth Hilton, and Philipp Kaldis*

Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute-Frederick, Frederick, MD 21702-1201

Monitoring Editor: Daniel Lew

Cdk1 was proposed to compensate for the loss of Cdk2. Here we present evidence that this is possible due to premature translocation of Cdk1 from the cytoplasm to the nucleus in the absence of Cdk2. We also investigated the consequence of loss of Cdk2 on the maintenance of the G1/S DNA damage checkpoint. Cdk2-/- mouse embryonic fibroblasts in vitro as well as regenerating liver cells after partial hepatectomy (PH) in Cdk2-/- mice, arrest promptly at the G1/S checkpoint in response to {gamma}-irradiation due activation of p53 and p21 inhibiting Cdk1. Furthermore reentry into S phase after irradiation was delayed in Cdk2-/- cells due to prolonged and impaired DNA repair activity. In addition, Cdk2-/- mice were more sensitive to lethal irradiation compared with wild type and displayed delayed resumption of DNA replication in regenerating liver cells. Our results suggest that the G1/S DNA damage checkpoint is intact in the absence of Cdk2, but Cdk2 is important for proper repair of the damaged DNA.

*Present address: Institute of Molecular and Cell Biology (IMCB), Cell Division and Cancer Laboratory (PRK), Proteos, Singapore 138673.

Address correspondence to: Philipp Kaldis (kaldis{at}imcb.a-star.edu.sg)






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