Functional Properties of the Herpes Simplex Virus Type I Origin-binding Protein Are Controlled by Precise Interactions with the Activated Form of the Origin of DNA Replication

Macao, Bertil; Olsson, Mariann; Elias, Per

doi:10.1074/jbc.m400371200

Cited by 16 publications

(18 citation statements)

References 42 publications

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“…The hairpin is stably bound, in a sequence-specific manner, by the C-terminal domain of OBP, and the single-stranded AT-rich spacer is contacted by the N-terminal helicase domains (Fig. 2) (26). A dimer of OBP can simultaneously bind two double-stranded DNA ligands but only one copy of a box I/box III hairpin with a 10-nucleotide single-stranded tail (26).…”

Section: Activation Of Origins Of Dna Replicationmentioning

confidence: 99%

“…A dimer of OBP can simultaneously bind two double-stranded DNA ligands but only one copy of a box I/box III hairpin with a 10-nucleotide single-stranded tail (26). It has been argued that this finding reflects a conformational change in OBP, from an origin-binding conformation to a helicase conformation, which can be facilitated by the interaction between ICP8 and the WPXXXGAXXFXXL motif found in the extreme C terminus of OBP (20,26). When ICP8 is in contact with ssDNA, this interaction can no longer be sustained (27).…”

Section: Activation Of Origins Of Dna Replicationmentioning

confidence: 99%

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Replication and Recombination of Herpes Simplex Virus DNA

Muylaert

Tang

Elias

2011

Journal of Biological Chemistry

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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...

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Section: Activation Of Origins Of Dna Replicationmentioning

confidence: 99%

Section: Activation Of Origins Of Dna Replicationmentioning

confidence: 99%

Replication and Recombination of Herpes Simplex Virus DNA

Muylaert

Tang

Elias

2011

Journal of Biological Chemistry

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“…Recruitment of ICP8 is probably also important for recruiting the rest of the replication complex. Finally, we note that our work principally concerns the proteins bound to duplex Box I and pays scant attention to the rearrangement of oriS and the possible binding of UL9 to a DNA hairpin formed from Box I and Box III, which is reported (3,17) to form upon activation of the origin, oriS.…”

Section: Discussionmentioning

confidence: 99%

“…In the presence of ICP8, UL9 will open dsDNA containing Box I, leading to a conformational change in the origin, thus facilitating unwinding (14 -16). As stated above, the changes in DNA conformation in the complete oriS may be more complex (3). Recently, it has been suggested that single-stranded oriS folds into a unique and evolutionarily conserved conformation, oriS*, which is stably bound by UL9.…”

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confidence: 99%

Structural and Biophysical Characterization of the Proteins Interacting with the Herpes Simplex Virus 1 Origin of Replication

Manolaridis

Mumtsidu

Konarev

et al. 2009

Journal of Biological Chemistry

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The C terminus of the herpes simplex virus type 1 originbinding protein, UL9ct, interacts directly with the viral singlestranded DNA-binding protein ICP8. We show that a 60-amino acid C-terminal deletion mutant of ICP8 (ICP8⌬C) also binds very strongly to UL9ct. Using small angle x-ray scattering, the low resolution solution structures of UL9ct alone, in complex with ICP8⌬C, and in complex with a 15-mer double-stranded DNA containing Box I of the origin of replication are described. Size exclusion chromatography, analytical ultracentrifugation, and electrophoretic mobility shift assays, backed up by isothermal titration calorimetry measurements, are used to show that the stoichiometry of the UL9ct-dsDNA 15-mer complex is 2:1 at micromolar protein concentrations. The reaction occurs in two steps with initial binding of UL9ct to DNA (K d ϳ 6 nM) followed by a second binding event (K d ϳ 0.8 nM). It is also shown that the stoichiometry of the ternary UL9ct-ICP8⌬C-dsDNA 15-mer complex is 2:1:1, at the concentrations used in the different assays. Electron microscopy indicates that the complex assembled on the extended origin, oriS, rather than Box I alone, is much larger. The results are consistent with a simple model whereby a conformational switch of the UL9 DNA-binding domain upon binding to Box I allows the recruitment of a UL9-ICP8 complex by interaction between the UL9 DNA-binding domains.The initiation of DNA replication for most double-stranded DNA (dsDNA) 6 viral genomes begins with the recognition of the origin by specific origin-binding proteins. The herpes simplex virus type 1 (HSV-1) genome encodes seven proteins required for origin-dependent DNA replication. These are the DNA polymerase (UL30) and its accessory protein (UL42), a heterotrimeric helicase-primase complex (UL5, UL8, and UL52), the single-stranded DNA-binding protein (ICP8 or UL29), and the origin-binding protein (UL9) (reviewed in Ref.1). HSV-1 contains three functional origins, oriL and two copies of oriS. OriS, which is about 80 bp in length, consists of three UL9 recognition sites, in Boxes I, II, and III, which are arranged in two overlapping palindromes (2). Box I and Box III are part of an evolutionarily conserved palindrome that forms a stable hairpin in single-stranded DNA, which may be important in the origin rearrangement (3) during initiation of replication. Box I and II are separated by an AT-rich spacer sequence, which varies in length and nucleotide composition between the different members of the ␣-herpesvirus subfamily (2, 4 -6).UL9 is a homodimer in solution, and EM studies, with UL9 bound to oriS, indicate the existence of a dimer or pair of dimers assembled on oriS (7). Several reports indicate that UL9 can physically interact not only with ICP8 (8) but also with other members of the HSV-1 replication complex, including UL8 (9) and UL42 (10). Thus UL9 functions as a docking protein to recruit these essential replication proteins to the viral origins. ICP8 stimulates the helicase activity of UL9 (11, 12) and binds to its C...

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“…Other viral mechanisms for initiation of DNA synthesis involve the creation of a site of initiation and are exemplified by adeno-associated virus (AAV), where the AAV Rep protein recognizes and nicks a stem-loop structure within the origin of replication (6). All of these proteins exhibit specific activity for nucleic acid binding to a sequence or structure within the lytic origin, and this activity consequently targets the protein to the site of DNA synthesis (20,21,24,35,40,42,45). The initiation of HCMV DNA replication appears to be more complex than that of other herpesviruses in that oriLyt spans nearly 3 kb and contains many cis-acting features such as transcription factor binding sites, RNA/DNA hybrid structures, and proposed stem-loop structures (2,25,32).…”

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confidence: 99%

Human Cytomegalovirus UL84 Interacts with an RNA Stem-Loop Sequence Found within the RNA/DNA Hybrid Region of ori Lyt

Colletti

Smallenburg

et al. 2007

J Virol

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Human cytomegalovirus (HCMV) lytic DNA replication is initiated at the complex cis-acting oriLyt region, which spans nearly 3 kb. DNA synthesis requires six core proteins together with UL84 and IE2. Previously, two essential regions were identified within oriLyt. Essential region I (nucleotides [nt] 92209 to 92573) can be replaced with the constitutively active simian virus 40 promoter, which in turn eliminates the requirement for IE2 in the origin-dependent transient-replication assay. Essential region II (nt 92979 to 93513) contains two elements of interest: an RNA/DNA hybrid domain and an inverted repeat sequence capable of forming a stem-loop structure. Our studies now reveal for the first time that UL84 interacts with a stem-loop RNA oligonucleotide in vitro, and although UL84 interacted with other nucleic acid substrates, a specific interaction occurred only with the RNA stem-loop. Increasing concentrations of purified UL84 produced a remarkable downward-staircase pattern, which is not due to a nuclease activity but is dependent upon the presence of secondary structures, suggesting that UL84 modifies the conformation of the RNA substrate. Cross-linking experiments show that UL84 possibly changes the conformation of the RNA substrate. The addition of purified IE2 to the in vitro binding reaction did not affect binding to the stem-loop structure. Chromatin immunoprecipitation assays performed using infected cells and purified virus show that UL84 is bound to oriLyt in a region adjacent to the RNA/DNA hybrid and the stem-loop structure. These results solidify UL84 as the potential initiator of HCMV DNA replication through a unique interaction with a conserved RNA stem-loop structure within oriLyt.The mechanism of initiation of human cytomegalovirus (HCMV) lytic DNA replication is largely undefined. The process of HCMV lytic DNA replication requires six core replication proteins: UL54 (polymerase), UL44 (polymerase accessory protein), UL57 (single-stranded DNA binding protein), UL70 (primase), UL102 (primase-associated factor), and UL105 (helicase) (13, 30). These six core proteins make up the generic replication machinery responsible for lytic DNA replication of the HCMV genome (27). Although the proposed activities of these components are postulated through homology to other herpesvirus systems, the exact mechanism of their assembly at the site of the origin is unknown. Our laboratory seeks to understand the early events in HCMV origin-dependent DNA replication that lead to the assembly and function of the HCMV DNA replication machinery.Most herpesviruses, as well as many other DNA viruses, encode an initiation factor, or origin binding protein (OBP), responsible for recognizing the lytic origin and creating a local environment where DNA is separated and the replication machinery can assemble. Many initiation proteins such as those for simian virus 40 (SV40) T antigen, papillomavirus E1, and herpes simplex virus type 1 (HSV-1) UL9 have enzymatic activities such as DNA-dependent nucleoside triphosphatase acti...

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Functional Properties of the Herpes Simplex Virus Type I Origin-binding Protein Are Controlled by Precise Interactions with the Activated Form of the Origin of DNA Replication

Cited by 16 publications

References 42 publications

Replication and Recombination of Herpes Simplex Virus DNA

Replication and Recombination of Herpes Simplex Virus DNA

Structural and Biophysical Characterization of the Proteins Interacting with the Herpes Simplex Virus 1 Origin of Replication

Human Cytomegalovirus UL84 Interacts with an RNA Stem-Loop Sequence Found within the RNA/DNA Hybrid Region of ori Lyt

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