cdc2 Cyclin-Dependent Kinase Binds and Phosphorylates Herpes Simplex Virus 1 U L 42 DNA Synthesis Processivity Factor

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Abstract
Earlier studies have shown that cdc2 kinase is activated during herpes simplex virus 1 infection and that its activity is enhanced late in infection even though the levels of cyclin A and B are decreased below levels of detection. Furthermore, activation of cdc2 requires the presence of infected cell protein no. 22 and the U L 13 protein kinase, the same gene products required for optimal expression of a subset of late genes exemplified by U S 11, U L 38, and U L 41. The possibility that the activation of cdc2 and expression of this subset may be connected emerged from the observation that dominant negative cdc2 specifically blocked the expression of U S 11 protein in cells infected and expressing dominant negative cdc2. Here we report that in the course of searching for a putative cognate partner for cdc2 that may have replaced cyclins A and B, we noted that the DNA polymerase processivity factor encoded by the U L 42 gene contains a degenerate cyclin box and has been reported to be structurally related to proliferating cell nuclear antigen, which also binds cdk2. Consistent with this finding, we report that (i) U L 42 is able to physically interact with cdc2 at both the amino-terminal and carboxyl-terminal domains, (ii) the carboxyl-terminal domain of U L 42 can be phosphorylated by cdc2, (iii) immunoprecipitates obtained with anti U L 42 antibody contained a roscovitine-sensitive kinase activity, (iv) kinase activity associated with U L 42 could be immunodepleted by antibody to cdc2, and (v) U L 42 transfected into cells associates with a nocodazole-enhanced kinase. We conclude that U L 42 can associate with cdc2 and that the kinase activity has the characteristic traits of cdc2 kinase.