Epstein Barr Virus (EBV) is causally related to Burkitt's Lymphoma, Hodgkin's Lymphoma, and Lymphoproliferative Diseases in immune suppressed and HIV infected people. In humans deficient in T cell immune responses, Latency III infected B-cells can be highly malignant. EBV conversion of Resting B Lymphocytes to continuously proliferating Lymphoblasts (LCLs) by expressing Latency III EBV nuclear antigens EBNA2, LP, 3A, 3C, and Latent Membrane Protein LMP1, is a relevant and experimentally useful model for EBV oncogenesis. EBNA3A and EBNA3C are essential for LCL growth and they regulate the expression of hundreds of cell genes. EBNA3A and EBNA3C bind to thousands of enhancer sites and alter enhancer-promoter looping. EBNA3A and 3C suppress CDKN2A/B p16INK4A and p14ARF expression to enable continuous cell proliferation. To further characterize the molecular mechanisms through which EBNA3A and EBNA3C regulate transcription, our specific aims are to: 1. Determine the effect of EBNA3A/3C on genome reorganization and their effect on LCL growth using Hi-C and ChIA-PET. 2. Determine the mechanisms through which EBNA3A/3C suppress senescence by examining the effect of EBNA3A/3C on enhancer/silencer promoter looping at the CDKN2A/B loci. 3. Determine the molecular mechanisms by which EBNA3A/C are tethered to DNA. These studies will provide new insights on how EBNA3A and EBNA3C contribute to EBV mediated growth transformation.

Public Health Relevance

Epstein Barr Virus (EBV) associated malignancies are a significant threat to humans. These studies will elucidate the molecular basis through which EBV proteins EBNA3A and EBNA3C exploit the normal B lymphocyte transcription program to achieve immortal growth and identify potential targets for intervention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA047006-33
Application #
9977926
Study Section
Virology - A Study Section (VIRA)
Program Officer
Daschner, Phillip J
Project Start
1987-06-01
Project End
2022-07-31
Budget Start
2020-08-01
Budget End
2021-07-31
Support Year
33
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
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