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Abolishment of the Tyr-15 Inhibitory Phosphorylation Site on cdc2 Reduces the Radiation-induced G₂ Delay, Revealing a Potential Checkpoint in Early Mitosis¹

Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104

cdc2 is inactivated before mitosis by phosphorylation at its inhibitory sites, Thr-14 and Tyr-15. Irradiation prevents HeLa cells from completing the G₂-M transition, and they arrest in G₂. Whereas phosphorylation at both of these sites occurs during the G₂ arrest, the individual role of each site in the G₂ delay has not previously been investigated. We have shown that the radiation-induced G₂ delay is preserved in wild-type or cdc2-AY-transfected cells (which retain Tyr-15); this delay is abolished in cdc2-TF- or cdc2-AF-transfected cells (which lack Tyr-15). Thus Tyr-15, but not Thr-14, appears to be essential for development of a G₂ delay after radiation. Abolishment of the G₂ delay by mutation at Tyr-15 resulted in the accumulation of cells with condensed chromatin and disrupted lamin B, suggesting that these cells may be blocked at a second G₂-M checkpoint in early mitosis (i.e., prophase). These data suggest (a) that the two inhibitory phosphorylation sites have distinct functions and that Tyr-15 phosphorylation, in particular, has a key role in the radiation-induced G₂ delay, and (b) that a second G₂-M checkpoint exists in early mitosis and that activation of this checkpoint by radiation prevents cells that enter mitosis from progressing further.

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