OVERALL Project Summary Abstract This program project grant application focuses on three DNA tumor viruses namely human papillomavirus (HPV), 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. EBV, HPV and KSHV are linked to multiple cancers in the human population. This proposal will study how these viruses promote carcinogenesis and investigate overarching biological principles. To identify the mechanisms responsible for the oncogenic properties of these viruses, the projects will characterize the basic molecular properties of these viruses as well as viral genes and proteins. They will investigate how these viruses modulate cellular processes including cell signaling pathways, epigenetic networks, and immune evasion. Furthermore, the potential therapeutic benefits of targeting these viruses will be tested in cell culture assays and animal models. This application consists of four projects and three cores. Project 1 will investigate the modulation of tumorigenesis by extracellular vesicles secreted from tumor virus-infected cells. Project 2 will investigate the role of long non-coding RNAs and R-loops in the lifecycle of oncogenic viruses. Project 3 will investigate how gammaherpesviruses evade host immune signaling pathways and the impact of host factors on viral lifecycles. Project 4 will examine the function of EBV-encoded lncRNAs and how EBV infection impacts tumorigenesis. Core A provides administrative support for the overall program. Core B provides state-of-the-art genomics and viral and cellular gene profiling, as well as biostatistics support for all the projects in this application, and Core C provides electron microscopy and mass photometry for structure studies.