Epstein-Barr virus (EBV) is a human tumor virus that is etiologically associated with nasopharyngeal cancer, Burkitt's, Hodgkin's and immunoblastic lymphoma and other human cancers. In all EBV-associated tumors the virus remains in a latent state of limited gene expression. The virus must be reactivated into its lytic cycle in order to spread between cells and among individuals. The Rta protein encoded in the EBV BRLF1 gene plays an obligatory role in mediating the switch between latency and lytic cycle gene expression. Our global objectives are to understand the complex mechanism of action of Rta and the control of BRLF1 expression. The proposed experiments are derived from many recent publications and new original unpublished observations made in our laboratory about the nature of Rta response elements, the mechanism of synergy between Rta and ZEBRA, the existence of a DNA binding inhibitory domain on Rta, and the role of global CpG methylation and histone H3 and H4 acetylation modifications in control of the promoter of BRLF1. Accordingly our AIMS are: 1) To analyze the mechanism by which Rta directly activates some promoters. 2) To study the mechanism of synergy between Rta and ZEBRA. 3) To understand the mechanism of a DNA binding inhibitory domain of Rta and the functional role of post-translational modification of Rta. 4) To investigate the importance of CpG methylation. 5) histone modification, and 6) cellular and viral activators on the response of BRLF1 to lytic cycle inducing stimuli. The experimental emphasis is on analysis of viral gene expression in the context of the behavior of the intact viral genome in cultured B cell tumors. The studies proposed address fundamental, though complex, issues of regulation of gene expression through the combinational action of cellular and viral proteins.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA016038-31A1
Application #
6989604
Study Section
Subcommittee G - Education (NCI)
Project Start
2004-09-02
Project End
2009-06-30
Budget Start
2004-09-02
Budget End
2005-06-30
Support Year
31
Fiscal Year
2004
Total Cost
$235,558
Indirect Cost
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Zhang, Pengwei; Monteiro da Silva, Gabriel; Deatherage, Catherine et al. (2018) Cell-Penetrating Peptide Mediates Intracellular Membrane Passage of Human Papillomavirus L2 Protein to Trigger Retrograde Trafficking. Cell 174:1465-1476.e13
Inoue, Takamasa; Zhang, Pengwei; Zhang, Wei et al. (2018) ?-Secretase promotes membrane insertion of the human papillomavirus L2 capsid protein during virus infection. J Cell Biol 217:3545-3559
Vallery, Tenaya K; Withers, Johanna B; Andoh, Joana A et al. (2018) Kaposi's Sarcoma-Associated Herpesvirus mRNA Accumulation in Nuclear Foci Is Influenced by Viral DNA Replication and Viral Noncoding Polyadenylated Nuclear RNA. J Virol 92:
Hayes, Karen E; Barr, Jamie A; Xie, Mingyi et al. (2018) Immunoprecipitation of Tri-methylated Capped RNA. Bio Protoc 8:
Park, Richard; Miller, George (2018) Epstein-Barr Virus-Induced Nodules on Viral Replication Compartments Contain RNA Processing Proteins and a Viral Long Noncoding RNA. J Virol 92:
Lipovsky, Alex; Erden, Asu; Kanaya, Eriko et al. (2017) The cellular endosomal protein stannin inhibits intracellular trafficking of human papillomavirus during virus entry. J Gen Virol 98:2821-2836
Singh, Gatikrushna; Fritz, Sarah M; Ranji, Arnaz et al. (2017) Isolation of Cognate RNA-protein Complexes from Cells Using Oligonucleotide-directed Elution. J Vis Exp :
Martinez, Ivan; Hayes, Karen E; Barr, Jamie A et al. (2017) An Exportin-1-dependent microRNA biogenesis pathway during human cell quiescence. Proc Natl Acad Sci U S A 114:E4961-E4970
Lee, Nara; Yario, Therese A; Gao, Jessica S et al. (2016) EBV noncoding RNA EBER2 interacts with host RNA-binding proteins to regulate viral gene expression. Proc Natl Acad Sci U S A 113:3221-6
DiMaio, Daniel (2016) Thank You, Edward. Merci, Louis. PLoS Pathog 12:e1005320

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