Replication and Recombination of Herpes Simplex Virus DNA

Abstract

Replication of herpes simplex virus takes place in the cell nucleus and is carried out by a replisome composed of six viral proteins: the UL30-UL42 DNA polymerase, the UL5-UL8-UL52 helicase-primase, and the UL29 single-stranded DNA-binding protein ICP8. The replisome is loaded on origins of replication by the UL9 initiator origin-binding protein. Virus replication is intimately coupled to recombination and repair, often performed by cellular proteins. Here, we review new significant developments: the three-dimensional structures for the DNA polymerase, the polymerase accessory factor, and the singlestranded DNA-binding protein; the reconstitution of a functional replisome in vitro; the elucidation of the mechanism for activation of origins of DNA replication; the identification of cellular proteins actively involved in or responding to viral DNA replication; and the elucidation of requirements for formation of replication foci in the nucleus and effects on protein localization.Herpesviruses are found in all animals from molluscs to man. During evolution, the viruses have become tightly associated and co-evolved with their hosts. They seem to cross species borders only by accident, and in such rare instances, they may cause unexpected and severe disease. Herpesviruses have an unusual lifestyle; they cause lytic infection in cells, leading to efficient production of new infectious virus particles, and they also establish latent infections in either non-dividing neuronal cells or cycling cells of the immune system. The latent state is characterized by expression of a very limited set of genes to ascertain maintenance of virus chromosomes and to escape recognition by the immune system. The mechanisms for establishing latency appear to differ considerably for different herpesviruses. In contrast, mechanisms for replication of virus DNA during lytic infection and subsequent formation of infectious particles seem to be evolutionarily conserved. There is one notable exception; the mechanism for recognition of origins of DNA replication and initiation of DNA synthesis differs between the herpesvirus families.Humans can be infected by eight different herpesviruses. Herpes simplex viruses I and II and varicella zoster virus are alphaherpesviruses. Cytomegalovirus and the roseoloviruses, human herpesviruses 6 and 7, are classified as betaherpesviruses. Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus belong to the gammaherpesvirus subfamily.In this minireview, we discuss recent developments in replication, recombination, and repair of herpes simplex virus DNA. We will take as our starting point a previous minireview in the Journal of Biological Chemistry that provides an insightful and accurate description of basic mechanisms and components of the herpes simplex virus replication machinery (1). Noteworthy new developments have been (i) the presentation of three-dimensional structures for the DNA polymerase, the polymerase accessory factor, and the single-stranded DNA-binding protein (ssDNA) 2 ; (ii) the recons...

Identification of Conserved Amino Acids in the Herpes Simplex Virus Type 1 UL8 Protein Required for DNA Synthesis and UL52 Primase Interaction in the Virus Replisome

“…Results presented above and previously published observations demonstrate direct interactions between UL8 and UL5-UL52 as well as ICP8 (1,8). It has also been suggested that UL8 interacts directly with OBP and the UL30 catalytic subunit of DNA polymerase (11,12).…”

New insights into replication origin characteristics in metazoans

“…DNA viruses are the smallest self-replicating entities, and specific palindromic sequences are required for their replication. 7,8 In most cases, the main initiating protein is encoded by the viral genome itself. Its binding to the Ori is also actively involved in the regulation of viral transcription and chromosomal segregation.…”

The Lytic Phase of Epstein-Barr Virus Requires a Viral Genome with 5-Methylcytosine Residues in CpG Sites

“…We hypothesized that if herpesviral DNA replication is fully functional in the absence of PCNA, DNMT1 could not be recruited to the replication forks of the herpesviral DNA. As herpesviruses overreplicate, i.e., amplify their DNA several hundredfold during the lytic phase (37,43), methylation marks at cytosine residues would be lost on both newly synthesized DNA strands, removing this epigenetic modification from EBV's genomic DNA, which had been acquired during latency.…”

“…Viral but not cellular factors mediate lytic herpesviral DNA replication (15,20,37). The function of PCNA in viral DNA replication is replaced by a structural homologue encoded by all herpesviruses, termed UL42 and BMRF1, in herpes simplex 1 and Epstein-Barr virus, respectively.…”