The program continues its focus on the human oncogenic herpesvirus, Epstein-Barr Virus (EBV) and Kaposi Sarcoma-associated Herpesvirus (KSHV) to identify the critical mechanisms by which these agents induce cancer and deregulate cell growth. To identify the mechanisms responsible for the oncogenic properties of these agents, the projects will characterize the basic molecular properties of viral proteins and their interactions with cellular proteins. In Project 1, Dr. Jack Griffith will continue his studies of the HSV recombinase complex consisting of ICP8 and UL12, and will apply the imaging skills that he has developed to analyze the structure of EBV and KSHV proteins and the association of KSHV proteins with DNA. Project 2 continues the study by Dr, Joseph Pagano on a novel deubiquitinase, UCHL1, whose expression is induced by EBV. This project will characterize the properties of this protein and in collaboration with Drs. Raab-Traub and Dittmer, determine its anti-growth properties in the mouse models that they have developed in Projects 4 and 5. Dr. Damania in Project 3 will develop systems to determine how KSHV induces angiogenesis, cell survival and migration. Drs. Raab-Traub and Dittmer in Projects 4 and 5 will develop and characterize the pathways that are essential for transformation and oncogenesis in transgenic murine models. The effects of EBV and KSHV on cellular miRNAs in the transgenic cancers will also be determined in both projects. A new core is requested, the Virogenomics Core, that will provide gene expression array support for all 5 projects on this program, profiling of the cellular miRNAs, and bioinformatic services for expression arrays and ChlP-Seq approaches.

Public Health Relevance

Epstein-Barr Virus and Kaposi Sarcoma Herpesvirus are linked to multiple human cancers. This proposal will study the viral proteins that are expressed in the cancers and that we have shown change the growth properties of cells inducing malignant properties. These experiments will identify how these proteins interact with cellular proteins to change their function. The requirement for these properties and the potential therapeutic benefit from blocking their functions will be tested in laboratory and animal models.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA019014-32A1
Application #
8152511
Study Section
Special Emphasis Panel (ZCA1-RPRB-0 (M1))
Program Officer
Daschner, Phillip J
Project Start
1997-05-01
Project End
2016-06-30
Budget Start
2011-07-27
Budget End
2012-06-30
Support Year
32
Fiscal Year
2011
Total Cost
$1,832,038
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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Bermek, Oya; Weller, Sandra K; Griffith, Jack D (2017) The UL8 subunit of the helicase-primase complex of herpes simplex virus promotes DNA annealing and has a high affinity for replication forks. J Biol Chem 292:15611-15621
Raab-Traub, Nancy; Dittmer, Dirk P (2017) Viral effects on the content and function of extracellular vesicles. Nat Rev Microbiol 15:559-572
Dyson, Ossie F; Pagano, Joseph S; Whitehurst, Christopher B (2017) The Translesion Polymerase Pol ? Is Required for Efficient Epstein-Barr Virus Infectivity and Is Regulated by the Viral Deubiquitinating Enzyme BPLF1. J Virol 91:

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