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abstract
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The studies described in this application for continuing support of a long term project center on the functions of the infected cell protein No. 22 (ICP22), a regulatory protein, in the biology and pathogenesis of herpes simplex viruses (HSV) infections. Our studies relevant to this proposal and its aims are as follows: (i) the 420-residue ICP22 is encoded by the a22 gene. The a22 open reading frame also encodes a second protein, Us1.5, consisting of the C-terminal 273 residues of ICP22. (ii) Mutants lacking the coding sequences of ICP22 or Us1.5 proteins are unable to replicate in mice but do replicate in cell culture in a cell type-dependent manner. (iii) No phenotype other than ability to replicate in mice has been mapped to the N-terminal domain of ICP22. Mutants lacking the coding sequence of Us 11 are attenuated and in culture accumulate grossly reduced levels of a subset of late viral proteins exemplified by Us11, UL41 and UL38. The objective of the studies proposed in this application is to continue studies of three functions mapped to the Us1.5 domain of the a22 gene. Specifically (i) In wild-type virus-infected cells, the accumulation of ICP22-dependent subset of late proteins is dependent on activation of the mitotic kinase cdc2, degradation of cdc2 kinase partners, cyclins A and B, the acquisition of a new partner, the UL42 DNA polymerase processivity factor, and finally, the ICP22-dependent binding and modification of topoisomerase IIa by the cdc2-UL42 protein complex. In uninfected cells cdc2 is normally activated by the cdc25C phosphatase, which is also activated in wild-type virus infected cells but not in ?a22-mutant virus-infected cells. Cdc2 is not activated in cdc25c-/- (knockout) cells. AIM 1 of this study is to determine whether HSV-1 activates cdc2 via an interaction of cdc25C-phosphatase with ICP22 and the UL13 protein kinase. The objective of AIM 2 is to investigate the role of the interaction of UL42 and topoisornerase IIa. (ii) ICP22 and UL13 mediate an aberrant phosphorylation of RNA POL II. We found that ICP22 interacts with cdk9, a T1 cyclin-dependent kinase involved in transcriptional activation. We have also shown that the C-terminal domain of RNA POL II is phosphorylated by cdk9 precipitates from wild type but nor from ?a22 mutant virus-infected cells. The objective of AIM 3 is to determine the role of ICP22 and cdk9 in the modification of RNA POL II. Lastly, (iii) our earlier studies have identified a cellular protein (p60) that binds both ICP22 and ICP0. A central question addressed in AIM 4 is the role of this protein in the biology of HSV-1. In all instances a key question to be resolved is the contribution of each of these functions of ICP22 to the biology of the virus in the experimental animal host.
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