Enzymatic Mechanism of Herpes Virus DNA Replication

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DESCRIPTION (provided by applicant): The aim of this research is to understand (i) the mechanism of initiation of herpes virus DNA replication, (ii) the mechanism of inversion that occurs during herpes virus DNA replication and (iii) the factors that influence the development of viral latency in herpes virus-infected neuronal cells. We anticipate that these studies will provide us with an insight into the replication, recombination and latency of a significant class of human pathogens. The investigation will be organized along the following lines. A. Analysis of the stimulation of binding of multimeric origin binding protein (UL9 protein) to Ori-s, an origin of HSV-1 DNA replication, by the cellular hTid-1 DnaJ chaperone. B. Role of neural F box protein (NFB42) in HSV- 1 latency. 1. Ubiquitination and degradation of UL9 protein upon binding NFB4 2. Investigation of state of phosphorylation of UL9 protein on its interaction with NFB42. C. Role of endonuclease G in the initiation of sequence inversion in the HSV- 1 genome. 1. Studies of a sequence cleavage by endonuclease G. 2. Effect of HSV- 1 infection on levels of endonuclease G. 3. Cellular localization of endonuclease G pre- and post HSV-1 infection 4. Interaction of endonuclease G with other proteins. 5. Effect of suppression of endonuclease G on a-sequence-mediated recombination.