scholarly journals Epstein-Barr Virus Nuclear Antigen 1 Does Not Cause Lymphoma in C57BL/6J Mice

2008 ◽  
Vol 82 (8) ◽  
pp. 4180-4183 ◽  
Author(s):  
Myung-Soo Kang ◽  
Vishal Soni ◽  
Roderick Bronson ◽  
Elliott Kieff
Keyword(s):  
Transgenic Mice ◽  
Epstein Barr Virus ◽  
Latent Infection ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Epstein Barr ◽  
Negative Controls ◽  
Mouse Lymphocytes

ABSTRACT To test whether transgenic Epstein-Barr virus nuclear antigen 1 (EBNA1) expression in C57BL/6 mouse lymphocytes causes lymphoma, EBNA1 expressed in three FVB lineages at two or three times the level of latent infection was crossed up to six successive times into C57BL/6J mice. After five or six crosses, 14/36, (38%) EBNA1 transgenic mice, 11/31 (36%) littermate EBNA1-negative controls, and 9/25 (36%) inbred C57BL/6J mice housed in the same facility had lymphoma. These data indicate that EBNA1 does not significantly increase lymphoma prevalence in C57BL/6J mice.

HAUSP/USP7 as an Epstein–Barr virus target

2004 ◽  
Vol 32 (5) ◽  
pp. 731-732 ◽  
Author(s):  
M.N. Holowaty ◽  
L. Frappier
Keyword(s):  
Epstein Barr Virus ◽  
Latent Infection ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
High Affinity ◽  
Cellular Immortalization ◽  
Epstein Barr ◽  
Epstein Barr Nuclear Antigen

USP7 (also called HAUSP) is a de-ubiquitinating enzyme recently identified as a key regulator of the p53–mdm2 pathway, which stabilizes both p53 and mdm2. We have discovered that the Epstein–Barr nuclear antigen 1 protein of Epstein–Barr virus binds with high affinity to USP7 and disrupts the USP7–p53 interaction. The results have important implications for the role of Epstein–Barr nuclear antigen 1 in the cellular immortalization that is typical of an Epstein–Barr virus latent infection.

scholarly journals Epstein–Barr virus nuclear antigen 3A partially coincides with EBNA3C genome-wide and is tethered to DNA through BATF complexes

2014 ◽  
Vol 112 (2) ◽  
pp. 554-559 ◽  
Author(s):  
Stefanie C. S. Schmidt ◽  
Sizun Jiang ◽  
Hufeng Zhou ◽  
Bradford Willox ◽  
Amy M. Holthaus ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Latent Infection ◽  
Protein Complexes ◽  
Nuclear Antigen ◽  
Lymphoblastoid Cell Lines ◽  
Barr Virus ◽  
Genome Wide ◽  
Epstein Barr

Epstein–Barr Virus (EBV) conversion of B-lymphocytes to Lymphoblastoid Cell Lines (LCLs) requires four EBV nuclear antigen (EBNA) oncoproteins: EBNA2, EBNALP, EBNA3A, and EBNA3C. EBNA2 and EBNALP associate with EBV and cell enhancers, up-regulate the EBNA promoter, MYC, and EBV Latent infection Membrane Proteins (LMPs), which up-regulate BCL2 to protect EBV-infected B-cells from MYC proliferation-induced cell death. LCL proliferation induces p16INK4A and p14ARF-mediated cell senescence. EBNA3A and EBNA3C jointly suppress p16INK4A and p14ARF, enabling continuous cell proliferation. Analyses of the EBNA3A human genome-wide ChIP-seq landscape revealed 37% of 10,000 EBNA3A sites to be at strong enhancers; 28% to be at weak enhancers; 4.4% to be at active promoters; and 6.9% to be at weak and poised promoters. EBNA3A colocalized with BATF-IRF4, ETS-IRF4, RUNX3, and other B-cell Transcription Factors (TFs). EBNA3A sites clustered into seven unique groups, with differing B-cell TFs and epigenetic marks. EBNA3A coincidence with BATF-IRF4 or RUNX3 was associated with stronger EBNA3A ChIP-Seq signals. EBNA3A was at MYC, CDKN2A/B, CCND2, CXCL9/10, and BCL2, together with RUNX3, BATF, IRF4, and SPI1. ChIP-re-ChIP revealed complexes of EBNA3A on DNA with BATF. These data strongly support a model in which EBNA3A is tethered to DNA through a BATF-containing protein complexes to enable continuous cell proliferation.

Ultrastructural Characterization of Hearts from Transgenic Mice Expressing the Epstein-Barr Virus Nuclear Antigen-Leader Protein

1999 ◽  
Vol 5 (S2) ◽  
pp. 1172-1173
Author(s):  
J.R. Megill ◽  
T. M. Monticello ◽  
M.H. French ◽  
P.L. Smith ◽  
N.C. Trippodo ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Epstein Barr Virus ◽  
Transgenic Line ◽  
Complex Life Cycle ◽  
Nuclear Antigen ◽  
Barr Virus ◽  
Nuclear Antigens ◽  
Leader Protein ◽  
Epstein Barr

Mice expressing the Epstein-Barr virus nuclear antigen-leader protein (EBNA-LP) develop congestive heart failure and atrial thrombosis as early as four months of age. Epstein-Barr virus (EBV) is a common human herpes virus with a complex life cycle involving chronic replication in epithelial tissues. The EBNA-LP, one of six EBV nuclear antigens, has an unknown biochemical function but is associated with EBV-induced growth transformation. This transgenic line was originally produced to investigate oncogenic consequences, but unexpectedly resulted in mice with progressive heart failure. Since the progression and development of the heart failure is highly predictable, this transgenic line may serve as a valuable model for studying the pathophysiologic changes associated with human dilated cardiomyopathy. We describe here the ultrastructural characteristics of the myocardium from EBNA-LP transgenic mice in order to better delineate the pathogenesis of the associated heart disease.

scholarly journals Structural Basis for Cooperative Binding of EBNA1 to the Epstein-Barr Virus Dyad Symmetry Minimal Origin of Replication

2019 ◽  
Vol 93 (20) ◽  
Author(s):  
Kimberly A. Malecka ◽  
Jayaraju Dheekollu ◽  
Julianna S. Deakyne ◽  
Andreas Wiedmer ◽  
Ursula D. Ramirez ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Epstein Barr Virus ◽  
Latent Infection ◽  
Nuclear Antigen ◽  
Plasmid Replication ◽  
Origin Of Replication ◽  
Replication Machinery ◽  
Barr Virus ◽  
Epstein Barr ◽  
Dyad Symmetry

ABSTRACTEpstein-Barr virus is associated with several human malignancies, including nasopharyngeal carcinoma, gastric cancer, and lymphoma. Latently infected cells carry a circularized EBV episome where the origin of replication (oriP) is comprised of two elements: the family of repeats (FR) and dyad symmetry (DS). The viral protein Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) binds to FR and DS to promote EBV episome maintenance and DNA replication during latent infection in proliferating cells. EBNA1 binding to the DS constitutes a minimal origin of DNA replication. Here we report the crystal structure of two EBNA1 DNA-binding domain dimers bound to a DS half-site. This structure shows that the DNA is smoothly bent, allowing for stabilizing interactions between the dimers. The dimer-dimer interface requires an intricate hydrogen bonding network involving residues R491 and D581. When this interface is disrupted, we note loss of stable dimer-dimer complex formation on the DNA, compromisedoriP-containing plasmid replication in cells, and impaired recruitment of the MCM3 complex to theoriP. Surface conservation analysis reveals that these residues are part of a larger conserved surface that may be critical for recruitment of replication machinery to theoriP. Our results reveal a new region of EBNA1 critical for its activity and one that may be exploited by targeted small molecules to treat EBV-associated disease.IMPORTANCEEpstein-Barr virus (EBV) is a causative agent of various malignancies and may also contribute to autoimmune disease. The latent and episomal form of the virus is known to drive EBV-associated oncogenesis. Persistence of the viral episome in proliferating tumor cells requires the interaction of Epstein-Barr virus nuclear antigen 1 (EBNA1) with the viral origin of plasmid replication (oriP). The dyad symmetry (DS) element inoriPis the essential minimal replicator oforiP. Here we report the X-ray crystal structure of EBNA1 bound to DS. The structure reveals a previous unrecognized interface formed between dimers of EBNA1 necessary for cooperative DNA binding, recruitment of cellular replication machinery, and replication function. These findings provide new insights into the mechanism of EBNA1 function at the replication origin and new opportunities to inhibit EBV latent infection and pathogenesis.

scholarly journals Structure-based design of small-molecule inhibitors of EBNA1 DNA binding blocks Epstein-Barr virus latent infection and tumor growth

2019 ◽  
Vol 11 (482) ◽  
pp. eaau5612 ◽  
Author(s):  
Troy E. Messick ◽  
Garry R. Smith ◽  
Samantha S. Soldan ◽  
Mark E. McDonnell ◽  
Julianna S. Deakyne ◽  
...  
Keyword(s):  
Dna Binding ◽  
Tumor Growth ◽  
Epstein Barr Virus ◽  
Transforming Growth Factor ◽  
Latent Infection ◽  
Viral Gene Expression ◽  
Nuclear Antigen ◽  
Viral Gene ◽  
Barr Virus ◽  
Epstein Barr

Epstein-Barr virus (EBV) is a DNA tumor virus responsible for 1 to 2% of human cancers including subtypes of Burkitt’s lymphoma, Hodgkin’s lymphoma, gastric carcinoma, and nasopharyngeal carcinoma (NPC). Persistent latent infection drives EBV-associated tumorigenesis. Epstein-Barr nuclear antigen 1 (EBNA1) is the only viral protein consistently expressed in all EBV-associated tumors and is therefore an attractive target for therapeutic intervention. It is a multifunctional DNA binding protein critical for viral replication, genome maintenance, viral gene expression, and host cell survival. Using a fragment-based approach and x-ray crystallography, we identify a 2,3-disubstituted benzoic acid series that selectively inhibits the DNA binding activity of EBNA1. We characterize these inhibitors biochemically and in cell-based assays, including chromatin immunoprecipitation and DNA replication assays. In addition, we demonstrate the potency of EBNA1 inhibitors to suppress tumor growth in several EBV-dependent xenograft models, including patient-derived xenografts for NPC. These inhibitors selectively block EBV gene transcription and alter the cellular transforming growth factor–β (TGF-β) signaling pathway in NPC tumor xenografts. These EBNA1-specific inhibitors show favorable pharmacological properties and have the potential to be further developed for the treatment of EBV-associated malignancies.

scholarly journals Structural, Functional, and Genetic Comparisons of Epstein-Barr Virus Nuclear Antigen 3A, 3B, and 3C Homologues Encoded by the Rhesus Lymphocryptovirus

2000 ◽  
Vol 74 (13) ◽  
pp. 5921-5932 ◽  
Author(s):  
Hua Jiang ◽  
Young-gyu Cho ◽  
Fred Wang
Keyword(s):  
B Cell ◽  
Transcriptional Activation ◽  
Rhesus Monkeys ◽  
Epstein Barr Virus ◽  
Latent Infection ◽  
Nuclear Antigen ◽  
In Vitro Assays ◽  
Barr Virus ◽  
Cell Immortalization ◽  
Epstein Barr

ABSTRACT EBNA-3A, -3B, and -3C are three latent infection nuclear proteins important for Epstein-Barr virus (EBV)-induced B-cell immortalization and the immune response to EBV infection. All three are hypothesized to function as transcriptional transactivators, but little is known about their precise mechanism of action or their role in EBV pathogenesis. We have cloned and studied the three EBNA-3 homologues from a closely related lymphocryptovirus (LCV) which naturally infects rhesus monkeys. The rhesus LCV EBNA-3A, -3B, and -3C homologues have 37, 40, and 36% amino acid identity with the EBV genes, respectively. Function, as measured by in vitro assays, also appears to be conserved with the EBV genes, since the rhesus LCV EBNA-3s can interact with the transcription factor RBP-Jκ and the rhesus LCV EBNA-3C encodes a Q/P-rich domain with transcriptional activation properties. In order to better understand the relationship between these EBV and rhesus LCV latent infection genes, we asked if the rhesus LCV EBNA-3 locus could be recombined into the EBV genome and if it could substitute for the EBV EBNA-3s when assayed for human B-cell immortalization. Recombination between the EBV genome and rhesus LCV DNA was reasonably efficient. However, these studies suggest that the rhesus LCV EBNA-3 locus was not completely interchangeable with the EBV EBNA-3 locus for B-cell immortalization and that at least one determinant of the species restriction for LCV-induced B-cell immortalization maps to the EBNA-3 locus. The overall conservation of EBNA-3 structure and function between EBV and rhesus LCV indicates that rhesus LCV infection of rhesus monkeys can provide an important animal model for studying the role of the EBNA-3 genes in LCV pathogenesis.

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