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.