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J Biol Chem, Vol. 274, Issue 49, 34779-34784, December 3, 1999

p34^Cdc2 Kinase Activity Is Excluded from the Nucleus during the Radiation-induced G₂ Arrest in HeLa Cells

Gary D. Kao, W. Gillies McKenna, and Ruth J. Muschel

From the Department of Radiation Oncology and  Department of Pathology and Lab Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104

The progression of cells from G₂ into mitosis is blocked by exposure to DNA-damaging agents such as ionizing radiation. This G₂ delay is associated with reduced cyclin B1-specific associated histone H1 kinase activity, increased inhibitory phosphorylation of p34^Cdc2, and depressed cyclin B1 levels in HeLa cells. Induction of cyclin B1 or expression of Cdc2AF, a mutant p34^Cdc2 that lacks the sites of inhibitory phosphorylation, only partially reverses the radiation-associated G₂ delay, although both maneuvers rapidly result in increased histone H1 kinase activity. To account for the persistent G₂ delay in the face of active p34^Cdc2 kinase, we determined the location of the kinase activity. Although p34^Cdc2 was active in the cytoplasm, the nuclear p34^Cdc2 was inactive. Irradiation led to nuclear accumulation of the inactive tyrosine-phosphorylated form of p34^Cdc2, whereas the active form was seen in the cytoplasm. At later times when cells had resumed cell cycle progression, nuclear kinase activity was detectable. These results give evidence of segregation of cytoplasmic and nuclear kinase activity after DNA damage that has the effect of enhancing checkpoint control. Shielding the nucleus from the potentially deleterious effects of kinase activity after DNA damage may help irradiated human cancer cells respond to irradiation.

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