EBNA-1: a protein pivotal to latent infection by Epstein-Barr virus

Leight, Elizabeth R.; Sugden, Bill

doi:10.1002/(sici)1099-1654(200003/04)10:2<83::aid-rmv262>3.0.co;2-t

Cited by 176 publications

(141 citation statements)

References 122 publications

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“…About 2 to 4% of cells continued to express CFP from an EBV episome at the end of 3 weeks. These findings are consistent with observations from previous studies in which plasmid DNA transfection was used to introduce EBV episomes (23). Leight and Sugden (23) estimated that the percentage of initially transfected cells able to maintain EBV episomes in a high percentage of daughter cells is between 1 and 10% under nonselective conditions.…”

Section: Discussionsupporting

confidence: 91%

“…The epigenetic mechanism underlying the efficient segregation of EBV episomes to daughter cells (23) remains to be elucidated. However, the interaction of EBNA-1-bound episomes with cellular chromosomes required for episome segregation during mitosis likely involves cellular proteins in addition to EBNA-1.…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

mentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…EBNA-1 is the only viral protein consistently expressed in all EBV-associated tumors (27). Its protein level of expression in EBV-positive cells appears to be regulated, because the number of molecules of EBNA-1 per cell is not proportional to the viral DNA present in those cells (28).…”

Section: Dom Neg 1 or 2 Do Not Affect Survival Of Ebv-negative Cells mentioning

confidence: 99%

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

Kennedy

Komano

Sugden

2003

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

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Epstein-Barr virus (EBV) has been causally associated with at least five human malignancies. The exact contributions made by EBV to these cancers remain unknown. We demonstrate that one viral protein found in all EBV-associated malignancies, Epstein-Barr nuclear antigen 1 (EBNA-1), is required for survival of one of these cancers, EBV-positive Burkitt's lymphoma. Inhibition of EBNA-1 decreases survival of these tumor cells by inducing apoptosis. Expression of EBNA-1 in uninfected cells also can inhibit apoptosis induced by expression of p53 in the absence of the EBV genome. Our findings demonstrate that EBNA-1 is critical for the continued survival of EBV-associated Burkitt's lymphoma, and, by extension, for the other B cell tumors with which EBV is associated. Efficient inhibitors of EBNA-1's functions would likely prove useful in the therapy of EBV-associated malignancies.

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“…Mounting a host immune response requires cleaving viral proteins to peptides and then presenting these as antigenic epitopes. The Epstein-Barr virus (EBV) 1 -encoded nuclear antigen 1 (EBNA1) protein of EBV is the sole viral protein required for genome replication in latent infections and is uniformly expressed in malignant cells that arise from EBV infection (3). Within the EBNA1 protein lies a long repetitive sequence composed exclusively of glycine and alanine residues.…”

mentioning

confidence: 99%

Repeat Sequence of Epstein-Barr Virus-encoded Nuclear Antigen 1 Protein Interrupts Proteasome Substrate Processing

Zhang

Coffino

2004

Journal of Biological Chemistry

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The Epstein-Barr virus thwarts immune surveillance through a Gly-Ala repeat (GAr) within the viral EpsteinBarr virus-encoded nuclear antigen 1 protein. The GAr inhibits proteasome processing, an early step in antigen peptide presentation, but the mechanism of proteasome inhibition has been unclear. By embedding a GAr within ornithine decarboxylase, a natural proteasome substrate that does not require ubiquitin conjugation, we now demonstrate inhibition in a purified system, excluding involvement of ubiquitin conjugation or of proteins extraneous to substrate and proteasome. We show further that the GAr acts as a stop-transfer signal in proteasome substrate processing, resulting in vivo in partial proteolysis that halts just short of the GAr. Similarly, introducing a GAr into green fluorescent protein destabilized by the ornithine decarboxylase degradation domain also stops the progress of proteolysis, leading to the accumulation of partial degradation products. We postulate that the ATP motor of the proteasome slips when it encounters the GAr, impeding further insertion and, in this way, halting degradation.

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EBNA-1: a protein pivotal to latent infection by Epstein-Barr virus

Cited by 176 publications

References 122 publications

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

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

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

Repeat Sequence of Epstein-Barr Virus-encoded Nuclear Antigen 1 Protein Interrupts Proteasome Substrate Processing

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