The aim of this research program is to understand in molecular detail the mechanism by which the replication of Herpes simplex- 1 (HSV-1) virus DNA is initiated and sustained. We propose to reconstitute in vitro with purified enzymes the orderly, semi- conservative replication of the HSV-1 genome. We expect that these studies should provide us with an insight into the mechanism by which replication of a eukaryotic genome is initiated. They should also yield information about the replication of a class of animal viruses that are of great public health importance. The investigation will be organized along the following lines: 1. Identification, purification and analysis of HSV-1 encoded replication proteins a. HSV-1 DNA polymerase b. HSV-1 single-stranded DNA binding protein (ICP8) c. HSV-1 induced replication factor(s) d. HSV-1 induced DNA helicase e. HSV-1 induced primase f. HSV-1 induced oriS binding protein g. Rolling circle DNA replication with purified proteins 2. Initiation of DNA replication at an HSV-1 origin (oriS) 3. In vitro inversion of HSV-1 L and S sequences

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National Institute of Allergy and Infectious Diseases (NIAID)
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Biochemistry Study Section (BIO)
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Stanford University
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Huang, Ke-Jung; Ku, Chia-Chi; Lehman, I Robert (2006) Endonuclease G: a role for the enzyme in recombination and cellular proliferation. Proc Natl Acad Sci U S A 103:8995-9000
Eom, Chi-Yong; Heo, Won Do; Craske, Madeleine L et al. (2004) The neural F-box protein NFB42 mediates the nuclear export of the herpes simplex virus type 1 replication initiator protein (UL9 protein) after viral infection. Proc Natl Acad Sci U S A 101:4036-40
Eom, Chi-Yong; Lehman, I Robert (2003) Replication-initiator protein (UL9) of the herpes simplex virus 1 binds NFB42 and is degraded via the ubiquitin-proteasome pathway. Proc Natl Acad Sci U S A 100:9803-7
Eom, Chi-Yong; Lehman, I Robert (2002) The human DnaJ protein, hTid-1, enhances binding of a multimer of the herpes simplex virus type 1 UL9 protein to oris, an origin of viral DNA replication. Proc Natl Acad Sci U S A 99:1894-8
He, X; Lehman, I R (2001) An initial ATP-independent step in the unwinding of a herpes simplex virus type I origin of replication by a complex of the viral origin-binding protein and single-strand DNA-binding protein. Proc Natl Acad Sci U S A 98:3024-8
He, X; Lehman, I R (2000) Unwinding of a herpes simplex virus type 1 origin of replication (Ori(S)) by a complex of the viral origin binding protein and the single-stranded DNA binding protein. J Virol 74:5726-8
Lee, S S; Lehman, I R (1999) The interaction of herpes simplex type 1 virus origin-binding protein (UL9 protein) with Box I, the high affinity element of the viral origin of DNA replication. J Biol Chem 274:18613-7
Lehman, I R; Boehmer, P E (1999) Replication of herpes simplex virus DNA. J Biol Chem 274:28059-62
Falkenberg, M; Elias, P; Lehman, I R (1998) The herpes simplex virus type 1 helicase-primase. Analysis of helicase activity. J Biol Chem 273:32154-7
Boehmer, P E; Lehman, I R (1997) Herpes simplex virus DNA replication. Annu Rev Biochem 66:347-84

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