The Herpesviridae comprise a large class of animal viruses of considerable public health importance. Of the Herpesviridae, replication of herpes simplex virustype-1 (HSV-1) has been the most extensively studied. The linear 152-kbp HSV-1 genome contains three origins of DNA replication and approximately 75 open-reading frames. Of these frames, seven encode proteins that are required for originspecific DNA replication. These proteins include a processive heterodimeric DNA polymerase, a single-strand DNA-binding protein, a heterotrimeric primosome with 5'-3' DNA helicase and primase activities, and an origin-binding protein with 3'-5' DNA helicase activity. HSV-1 also encodes a set of enzymes involved in nucleotide metabolism that are not required for viral replication in cultured cells. These enzymes include a deoxyuridine triphosphatase, a ribonucleotide reductase, a thymidine kinase, an alkaline endo-exonuclease, and a uracil-DNA glycosylase. Host enzymes, notably DNA polymerase alpha-primase, DNA ligase I, and topoisomerase II, are probably also required. Following circularization of the linear viral genome, DNA replication very likely proceeds in two phases: an initial phase of theta replication, initiated at one or more of the origins, followed by a rolling-circle mode of replication. The latter generates concatemers that are cleaved and packaged into infectious viral particles. The rolling-circle phase of HSV-1 DNA replication has been reconstituted in vitro by a complex containing several of the HSV-1 encoded DNA replication enzymes. Reconstitution of the theta phase has thus far eluded workers in the field and remains a challenge for the future.

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SummaryHerpesviruses are large double stranded DNA animal viruses with the distinguishing ability to establish latent, life-long infections. To date, eight human herpesviruses that exhibit distinct biological and corresponding pathological/clinical properties have been identified. During their life cycles, herpesviruses execute an intricate chain of events geared towards optimizing their replication. This sets an interesting paradigm to study fundamental biological processes. This review summarizes recent developments in herpesvirus research with emphasis on genome transactions, particularly with respect to the prototypic herpes simplex virus type-1. IUBMB Life, 55: 13-22, 2003

We had previously demonstrated that the 40 origin have shown that origin-specific initiation of DNA replication involves protein-mediated destabilization ofthe DNA duplex at the origin, thereby allowing access of the DNA synthetic machinery to the DNA (4). For simian virus 40, the initiator protein, large tumor antigen, recognizes elements within the origin of replication and leads to the destabilization of the DNA duplex through its DNA helicase activity. This process also requires the action ofthe cellular SSB, RP-A, to maintain the DNA in a single-stranded conformation (2, 5, 6).The ability of HSV-1 UL9 protein to recognize elements within the HSV-1 origin ofreplication (2, 3, 7) and to function as a DNA helicase (8, 9) suggests that it is involved in origin-specific DNA unwinding during HSV-1 DNA replication. Origin-unwinding and the maintenance of the singlestranded conformation should be aided by the helixdestabilizing properties of the HSV-1-encoded SSB ICP8 (10). Consequently, efficient destabilization of the DNA duplex at the origin might be expected to involve the concerted action of the UL9 protein and ICP8.We had reported (9) that ICP8 can specifically stimulate the DNA helicase activity ofUL9 protein. We show here that thisThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.functional stimulation is due to the tight interaction between ICP8 and UL9 protein.

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