Fidelity of Herpes Simplex Virus DNA Replication

Fidelity of Herpes Simplex Virus DNA Replication

The herpes simplex virus (HSV) single-stranded DNA-binding protein, ICP8, is required for viral DNA synthesis. HSV-1 DNA replication is thought to occur in two stages: origin-dependent DNA replication (stage I) mediated by the origin binding protein (OBP), followed by origin- and OBP-independent DNA replication (stage II). In contrast, it has been proposed that the herpesvirus replication machinery might replicate AAV DNA. Wilkinson and S. Lagging strand products (∼0.2 to 0.6 kb) were significantly shorter than leading strand products (∼2 to 10 kb), and conditions that stimulated primer synthesis led to shorter lagging strand products. Inversion of adjacent L segments in HSV concatemers has been observed 3 to 4 h after infection, when replicating DNA is still devoid of free genomic termini (34). Notably, p130−/−/p107−/− double-knockout cells had a virus replication phenotype intermediate between those of the p107−/− and p130−/− cells.

Fidelity of Herpes Simplex Virus DNA Replication
Factors governing these steps are the Pol’s identity and the sequence contexts. Our findings suggest that ICP8 by its strong ssDNA‐binding activity exploits the unique single‐strandedness of the AAV genome to form a tripartite complex with Rep78 and AAV ssDNA. The exact mechanisms by which these proteins act in concert to initiate and efficiently replicate the HSV-1 genome in the infected cell are poorly understood. In wild-type HSV-1-infected cells, AAV replication compartments and PML NBs did not coexist, presumably because PML was completely disrupted by the HSV-1 ICP0 protein. Whereas the identity of the catalytic subunit of the Pol is an important factor in replication fidelity, it appears that the UL42 subunit of the HSV- 1 Pol complex also can affect the DNA replication fidelity. Since the development of herpes simplex virus (HSV)-based packaging systems for recombinant AAV vectors (1) the interaction of AAV with its helper virus HSV has raised increasing interest. ?

(1). The smaller-than-unit-length products are representative of the entire HSV genome, indicating that alkaline nuclease is not inhibited at specific sequences. ? (2). Roles of UL42 accessory protein of the HSV-1 Pol in DNA replication fidelity. ? (3).

Position effects of the target gene in replication fidelity. ? Results will be critical to the understanding of the molecular mechanisms regulating DNA replication fidelity of both HSV-1 and eukaryotes, and of the structure-functional relationship of HSV-1 Pol. This study also will be of value for the design of new antiviral drugs and treatments. ? ? The DNA binding domain is represented by the hatched region.

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