A putative origin of replication of plasmids derived from Epstein-Barr virus is composed of two cis-acting components.

Reisman, David; Yates, John L.; Sugden, Bill

doi:10.1128/mcb.5.8.1822

Cited by 436 publications

(406 citation statements)

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“…The cis-acting oriP (the latent viral DNA replication origin) sequence, which contains FR (family of repeat) and DS (dyad symmetry), and the trans-acting EBV nuclear antigen-1 (EBNA-1) are required for EBV latent infection, which is characterized by autonomous replication and nuclear retention of the EBV genome in host cells. [5][6][7] From the viewpoint of sustained gene expression, a gene delivery vector based on EBV has been constructed. 8 However, this EBV vector can transfer genes to B lymphocytes but not to other somatic cells.…”

Section: Introductionmentioning

confidence: 99%

Sustained transgene expression in vitro and in vivo using an Epstein–Barr virus replicon vector system combined with HVJ liposomes

et al. 1998

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For long-term gene expression in tissues, we constructed chromosomally in BHK-21 cells. In human cells, transforman Epstein-Barr virus (EBV) replicon-based plasmid, pEB, ation was five to 20 times more efficient with pEBc than containing the latent viral DNA replication origin (oriP) and with pcDNA3, and 18-35% of the introduced EBV replicon EBV nuclear antigen-1 (EBNA-1). When pEB was transplasmid was replicated autonomously. The luciferase gene ferred to human cells (HeLa-S3, HEK 293 and FS 3) and or lacZ gene was introduced into mouse liver using HVJrodent cells (BHK-21) using HVJ-cationic liposomes, AVE liposomes. Luciferase gene expression was observed luciferase expression was observed in those cells for at for at least 35 days in cells transfected with pEBActLuc, least 10 days. Luciferase activity was two to 10 times whereas it was not detected on day 14 in cells transfected higher in those cell lines on and after day 3 post-transfecwith pActLuc, which lacks the EBV sequence. By the transtion of pEBActLuc compared with plasmids without the fer of pEBActNlacF, the lacZ gene expression rate in hepa-EBV replicon sequence. Southern blot analysis showed tocytes was approximately 35 and 12% on days 7 and that the pEB vector luciferase gene was maintained extra-35, respectively.

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Section: Introductionmentioning

confidence: 99%

Sustained transgene expression in vitro and in vivo using an Epstein–Barr virus replicon vector system combined with HVJ liposomes

et al. 1998

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“…Both mechanisms require the interaction of EBV nuclear antigen 1 (EBNA-1) protein with the EBV origin of replication (oriP) (23). oriP consists of two groups of EBNA-1 binding sites, the family of repeats (FR) and the dyad symmetry element (DS) (31,43). The FR is composed of 20 imperfect copies of a 30-bp repeat, each one able to bind an EBNA-1 dimer.…”

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confidence: 99%

Development of a Novel Helper-Dependent Adenovirus-Epstein-Barr Virus Hybrid System for the Stable Transformation of Mammalian Cells

Dorigo

Gil

Gallaher

et al. 2004

J Virol

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Epstein-Barr virus (EBVEpstein-Barr virus (EBV) is a gammaherpesvirus that preferentially infects human B lymphocytes (16,17,26). The latent form of EBV is capable of lifelong persistence as a circular episome in human B cells. Stable maintenance of the 165-kb EBV episome is conferred mainly by the abilities of EBV episomes to replicate once per S phase and to segregate efficiently into daughter cells during cell division (44). Both mechanisms require the interaction of EBV nuclear antigen 1 (EBNA-1) protein with the EBV origin of replication (oriP) (23). oriP consists of two groups of EBNA-1 binding sites, the family of repeats (FR) and the dyad symmetry element (DS) (31, 43). The FR is composed of 20 imperfect copies of a 30-bp repeat, each one able to bind an EBNA-1 dimer. The binding of EBNA-1 to the FR forms a bridge between chromosomes and oriP-containing plasmids (25). During mitosis, EBV episomes are tethered to metaphase chromosomes through EBNA-1, allowing the efficient segregation of episomes to daughter cells. The association of EBNA-1 with the FR also increases the nuclear import and retention of EBV plasmids and may target the plasmids to nuclear regions conducive to the efficient expression of EBV episome sequences (20).The DS consists of four copies of the EBNA-1 binding site (43). Upon binding of EBNA-1 through its C-terminal domain, the DS confers the initiation of DNA replication once per S phase (17). In the absence of the DS, EBV episomes fail to undergo replication unless they contain a different source of a replication origin, such as human genomic DNA. Krysan et al. (19) showed that replacement of the DS in EBV plasmids with large human chromosomal fragments resulted in efficient replication and segregation. Further studies demonstrated that the size of the genomic insert affected replication efficiency, favoring inserts of about 20 kb in length (12). EBV plasmids containing human genomic DNA were shown to replicate efficiently in rodent cells, in contrast to plasmids containing EBV-derived oriP (18). The transformation of various cell lines with EBV episomes in vitro has revealed the potential to confer long-term transgene expression and correct genetic defects in deficient cell lines (3,15,18,21,44).The delivery of EBV episomes is commonly performed by transfection. However, for quantitative delivery of EBV episomes, particularly in vivo, different techniques are required. Adenovirus recombinants have been shown to efficiently infect a wide variety of mammalian cells and tissues in vitro and in vivo (1). The expression of transgenes from adenovirus vectors is usually temporary, since the adenovirus DNA remains episomal in the majority of infected cells and is only integrated and therefore stably maintained at a frequency of 0.01 to 1% (11). In vivo, immune responses against viral antigens can cause the elimination of infected cells (8,30,41). Compared to first-generation adenovirus recombinants, helper-dependent adenovirus (HDA) vectors have no viral coding sequences and

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“…Initial genetic dissections of EBV identified one viral protein, Epstein-Barr Nuclear Antigen 1 (EBNA1), and one region of the viral genome, termed oriP, as being necessary and sufficient for replication of the viral plasmid (Yates, Warren et al 1984) (Lupton and Levine 1985;Reisman, Yates et al 1985), (Reisman and Sugden 1986). oriP is composed of two separable cis elements, the Family of Repeats (FR) and the Dyad Symmetry element (DS) (Baer, Bankier et al 1984;Reisman, Yates et al 1985), which both contain binding sites for EBNA1 in vitro (Rawlins, Milman et al 1985) (Harrison, Fisenne et al 1994), and in vivo (Hsieh, Camiolo et al 1993), (Niller, Glaser et al 1995) (Figure 1). FR is composed of 21 imperfect copies of a 30bp repeat and contains 20 high affinity EBNA1-binding sites (Figure 1).…”

Section: Cis Elements Of Ebv That Contribute To Dna Replicationmentioning

confidence: 99%

“…Insertions of 3, 5, or 10bp between the paired sites do not support DNA replication either (Harrison, Fisenne et al 1994). Additionally, pairs of EBNA1-binding sites within the EBV genome that have center-to-center spacings other than 21bp, such as in FR (with 30bp spacing) and near the Q promoter (with 24bp spacing) (Figure 1.A), do not support DNA replication (Reisman, Yates et al 1985), (Aiyar, Tyree et al 1998), (Yates, Camiolo et al 2000). The functional roles of the elements within DS have been confirmed by studies of another region of EBV's genome, termed Rep*, which was identified as an element that can substitute for DS inefficiently (Kirchmaier and Sugden 1998).…”

Section: Cis Elements Of Ebv That Contribute To Dna Replicationmentioning

confidence: 99%

“…Single cell analyses have shown that DS is a highly-efficient origin; at least 84% of plasmids carrying oriP in cis in HeLa cells expressing EBNA1 are duplicated in each S-phase (Nanbo, Sugden et al submitted). DS contains four EBNA1-binding sites, albeit with lower affinity than those found in FR (Reisman, Yates et al 1985). The topology of DS is such that the four binding sites are arranged as two pairs of sites, with 21bp centerto-center spacing between each pair and 33bp center-to-center spacing between the two nonpaired internal binding sites (Figure 1.C) (Baer, Bankier et al 1984;Rawlins, Milman et al 1985).…”

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The plasmid replicon of Epstein–Barr virus: Mechanistic insights into efficient, licensed, extrachromosomal replication in human cells

Lindner

Sugden

2007

Plasmid

103

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The genome of Epstein-Barr Virus (EBV) and plasmid derivatives of it are among the most efficient extrachromosomal replicons in mammalian cells. The latent origin of plasmid replication (oriP), when supplied with the viral Epstein-Barr Nuclear Antigen 1 (EBNA1) in trans, provides efficient duplication, partitioning and maintenance of plasmids bearing it. In this review, we detail what is known about the viral cis and trans elements required for plasmid replication. In addition, we describe how the cellular factors that EBV usurps are used to complement the functions of the viral constituents. Finally, we propose a model for the sequential assembly of an EBNA1-dependent origin of DNA synthesis into a pre-Replicative Complex (pre-RC), which functions by making use only of cellular enzymatic activities to carry out the replication of the viral plasmid. KeywordsoriP; EBNA1; EBV; origin; DS; Rep* General BackgroundEpstein-Barr Virus (EBV), a member of the herpesvirus family, is a surprisingly successful parasite, as are other human members of this family of viruses. It establishes a persistent, lifelong infection in greater than 90% of the world's population (Fields, Knipe et al. 2006). Primary infection by EBV causes infectious mononucleosis in some, usually adolescent people (Evans, Niederman et al. 1968). The latent cycle of the virus that follows infection is usually asymptomatic in the host, however in a small fraction of infected people, EBV contributes to several cancers including Burkitt's lymphoma, some T-cell lymphomas, Hodgkin's disease, post-transplant lymphoproliferative disease, nasopharyngeal carcinoma, and gastric carcinoma. EBV was the first human virus to be classified as a tumor virus (reviewed in Chapter 75 of (Fields, Knipe et al. 2006)) and has been studied because of its association with these diseases. EBV, in addition, has also served as a model to study DNA replication in human cells because of it's ability both to maintain its genome as an extrachromosomal replicon in infected B-cells, and to appropriate the cellular DNA replication machinery needed for its licensed replication.* To whom correspondence should be addressed: 1400 University Ave, Madison, WI 53706, Phone: 608.262.6697, Fax: 608.262.2824, Email: sugden@oncology.wisc.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Cis Elements of EBV that Contribute to DNA ReplicationThe genome of EBV is approximately 165kbp (Bloss and Sugden 1994) and resides as a nucleosome-coated nuclear plasmid in infected cells (Wensing and Farrell 2000), (Shaw, Levinger et al. 1979)...

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A putative origin of replication of plasmids derived from Epstein-Barr virus is composed of two cis-acting components.

Cited by 436 publications

References 40 publications

Sustained transgene expression in vitro and in vivo using an Epstein–Barr virus replicon vector system combined with HVJ liposomes

Sustained transgene expression in vitro and in vivo using an Epstein–Barr virus replicon vector system combined with HVJ liposomes

Development of a Novel Helper-Dependent Adenovirus-Epstein-Barr Virus Hybrid System for the Stable Transformation of Mammalian Cells

The plasmid replicon of Epstein–Barr virus: Mechanistic insights into efficient, licensed, extrachromosomal replication in human cells

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