Epstein-Barr virus provides a survival factor to Burkitt's lymphomas

Kennedy, Gregory D.; Komano, Jun; Sugden, Bill

doi:10.1073/pnas.2336099100

Cited by 236 publications

(205 citation statements)

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“…The protein also acts as a transcriptional regulator of both viral and host promoters and may promote lytic reactivation of the virus (5,6). Furthermore, multiple lines of evidence indicate that EBNA1 contributes to the development of EBV associated tumours through increasing cell proliferation and survival and possibly by inducing oxidative stress (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Modelling the structure of full-length Epstein–Barr virus nuclear antigen 1

2014

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Abstract:Epstein-Barr virus (EBV) is a clinically important human virus associated with several cancers and is the etiologic agent of infectious mononucleosis. The viral nuclear antigen-1 (EBNA1) is central to the replication and propagation of the viral genome and likely contributes to tumourigenesis. We have compared EBNA1 homologues from other primate lymphocryptoviruses (LCV) and found that the central glycine/alanine repeat (GAr) domain, as well as predicted cellular protein (USP7 and CK2) binding sites are present in homologues in the Old World primates, but not the marmoset; suggesting that these motifs may have co-evolved. Using the resolved structure of the C-terminal one third of EBNA1 (homodimerisation and DNA binding domain), we have gone on to develop monomeric and dimeric models in silico of the full length protein.The C-terminal domain is predicted to be structurally highly similar between homologues, indicating conserved function. Zinc could be stably incorporated into the model, bonding with two N-terminal cysteines predicted to facilitate multimerisation. The GAr contains secondary structural elements in the models, while the protein binding regions are unstructured, irrespective of the prediction approach used and sequence origin. These intrinsically disordered regions may facilitate the diversity observed in partner interactions. We hypothsise that the structured GAr could mask the disordered regions, thereby protecting the protein from default degradation. In the dimer conformation, the C-terminal tails of each monomer wrap around a proline-rich protruding loop of the partner monomer, providing dimer stability, a feature which could be exploited in therapeutic design. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation EBV-B95-8 hu-EBNA1CyEBV-TsBB6 cy-EBNA1 CeHV15 rh-EBNA1CeHV12 ba-EBNA1 CalHV3 ma EBNA1Modelling the structure of full length Epstein-Barr Virus Nuclear Antigen Figure S2. EBNA1 model comparison.The EBV B95-8 EBNA1 sequence was input to I-TASSER, which selected the EBNA1 C-terminal domain crystal structure (1B3T) and several fragment templates comprising: yeast fatty acid synthetase (2PFF), a-L-fucosidase (2Z8X), photosynthetic reaction centre (1C51), type A collagen (1YOF) and dimeric 6-phosphoglucouronate dehydrogenase (2ZYD). The 1B3T template was also used to generate models in MOE. EBNA1 models constructed using I-TASSER and MOE (and the composite of these two generated in Modeller9v8 (shown above), were assessed for structural plausibility using Molprobity and QMEAN score servers (table S1). Models were superimposed over the template (1B3T) and RMSD was estimated for each. The qualitative model energy analysis, normalised (QMEANnorm) score of a protein structural model provides a composite scoring function based on several geometrical aspects, both global (for the entire structure) and local (per residue), enabling the discrimination of good and bad models. The human and other primate LCV EBNA1 protein structure models (as indicated) were ...

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Section: Introductionmentioning

confidence: 99%

Modelling the structure of full-length Epstein–Barr virus nuclear antigen 1

2014

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“…The ''inverse relationship between the levels of detectable EBNA1 and the penetrance of disease'' (40) with E PyP-EBNA1 could have been due to a cis-acting E PyP effect on expression of a putative cellular oncogene in the lineage with uniform lymphoma mortality. Indeed, EBNA1 expression in primary or continuous cells in culture has been associated with relatively small effects on cell growth, survival, or gene expression (29,(37)(38)(39)(43)(44)(45). We therefore initiated a series of EBNA1-transgenic mouse experiments to study the effect of EBNA1 protein in mouse B lymphocytes at levels similar to that of latent EBV infection in human B lymphocytes.…”

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confidence: 99%

“…Moreover, EBNA1 has little effect on transcription of an EBNA1-dependent reporter integrated at most sites in cell DNA (20,29). Alternatively, EBNA1 might alter cell growth or survival through an interaction with a cell protein (30)(31)(32)(33)(34)(35)(36)(37)(38)(39). However, once EBV DNA has integrated into cell DNA, EBNA1 is not required for LCL growth, and LCLs with EBNA1-null mutant EBV genomes are indistinguishable from wild-type EBV-transformed B lymphocytes in their growth (12).…”

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confidence: 99%

Epstein-Barr virus nuclear antigen 1 does not induce lymphoma in transgenic FVB mice

Kang

Yasui

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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The lymphoma-inducing potential of Ig heavy-chain enhancer-and promoter-regulated Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) was evaluated in three transgenic FVB mouse lineages. EBNA1 was expressed at a higher level in transgenic B220(؉) splenocytes than in EBV-infected lymphoblastoid cell lines. EBNA1 was also expressed in B220(؊) transgenic splenocytes and thymocytes. Before killing and assessments at 18 -26 months, EBNA1-transgenic mice did not differ from control mice in mortality. At 18 -26 months EBNA1-transgenic mice did not differ from littermate control in ultimate body weight, in spleen size or weight, in lymph node, kidney, liver, or spleen histology, in splenocyte fractions positive for cluster of differentiation (CD)3 , CD4, CD8, CD62L, B220, CD5, IgM, IgD, MHC class II, CD11b, or CD25, or in serum IgM, IgG, or total Ig levels. Lymphomas were not found in spleens or other organs of 18-to 26-month-old EBNA1-transgenic (n ‫؍‬ 86) or control (n ‫؍‬ 45) FVB mice. EBNA1-transgenic lineages had a higher pulmonary adenoma prevalence than did littermate controls (39% versus 7%). However, the adenoma prevalence was not higher in EBNA1-transgenic mice than has been described for FVB mice, and EBNA1 was not expressed in normal pulmonary epithelia or adenomas.cancer ͉ herpesvirus ͉ latent ͉ persistence I n initial lymphocyte infection, Epstein-Barr Virus (EBV) causes B lymphocyte proliferation through a latency III program of expression of six nuclear proteins (EBNAs), two different integral membrane proteins, two small RNAs, and Bam A-initiated transcripts (1, 2). Although, in vitro, latency III-infected lymphocytes are able to grow endlessly as lymphoblastoid cell lines (LCLs), EBV proteins expressed in latency III-infected cells, in vivo, engender T cell responses that limit infected cell survival. EBV mostly persists long term in nonproliferating, latency I-or II-infected B cells that express EBNA1 or EBNA1 and latent infection membrane proteins, respectively (2-4). Latency I or latency II are also characteristic of Burkitt's lymphoma, Hodgkin's disease, and nasopharyngeal carcinoma (2). EBNA1 is expressed in almost all latent EBV infections and associated malignant diseases.EBNA1 enables efficient EBV episome replication, transcription, and maintenance in latently infected dividing cells (5-21). EBNA1 amino acids 379-641 include a dimerization and DNAbinding domain, which binds cognate 30-bp inverted repeat DNA sequences. EBV origin of plasmid replication (oriP) consists of 20 tandem cognate 30-bp repeats and four others 1 kbp away in a dyad symmetry (22). OriP has intrinsic origin activity. EBNA1 enhances oriP-dependent episome replication, transcription, and maintenance (7,8). EBNA1 amino acids 1-378 are necessary for chromosome association, transcriptional enhancement, and episome persistence, although not for initial DNA replication (21,(23)(24)(25). Within amino acids 1-378 is an irregular glycine͞alanine repeat, which inhibits EBNA1 processing through the proteasome͞TAP pathway (26,27).Becau...

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“…This shift in promoter usage correlates with the transcription of several viral genes and a prevention of the infected cell from dying by apoptosis, events likely underlying the role of transcriptional activation by UR1 in transforming infected B-cells. Additionally, UR1 is necessary for the continuing survival of EBV-positive B-cells; derivatives of EBNA1 lacking UR1 function as dominant-negative mutants and inhibit cell survival (Kennedy, Komano et al 2003).…”

Section: Ebna1: the Sole Trans-acting Element Of Ebv Required For Itsmentioning

confidence: 99%

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

Lindner

Sugden

2007

Plasmid

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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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Epstein-Barr virus provides a survival factor to Burkitt's lymphomas

Cited by 236 publications

References 43 publications

Modelling the structure of full-length Epstein–Barr virus nuclear antigen 1

Modelling the structure of full-length Epstein–Barr virus nuclear antigen 1

Epstein-Barr virus nuclear antigen 1 does not induce lymphoma in transgenic FVB mice

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

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