Characterizing the Molecular Mode of Action of EBV Noncoding RNA EBER1

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PROJECT SUMMARY Epstein-Barr virus (EBV) was the first human cancer-causing virus to be discovered. EBV primarily infects lymphocytes and epithelial cells, which can result in a wide range of lymphomas and carcinomas, respectively. Over 90% of the world’s population is infected with this virus, but infection is mostly asymptomatic in healthy individuals. The cancer-causing potential of EBV becomes evident particularly in immunocompromised individuals, e.g. transplant recipients who are under long-term administration of immune-suppressing medication, where reactivation of the virus can drive tumor formation. Apart from viral proteins, EBV expresses two highly abundant noncoding RNAs called EBER1 and EBER2. Both noncoding RNAs exhibit a strict nuclear localization and are expressed at high levels on par with other greatly abundant host noncoding RNAs that carry out vital cellular functions. It can be assumed based on this high copy number as well as the fact that EBERs are found in all clinical isolates of EBV that EBERs execute or interfere with a vital cellular process during infection. While we have made significant progress in elucidating the molecular mechanism by which EBER2 benefits the EBV life cycle, the molecular function of EBER1 remains enigmatic. Given the vast parallels between both EBER1 and EBER2, we hypothesize that EBER1 may also execute a similar function to EBER2, i.e. to bind to specific sites on chromatin and regulate gene expression. Here we propose to apply cutting-edge techniques combining aptamer technology and next- generation sequencing to further our insight into the molecular mechanism of EBER1. Furthermore, we have recently obtained experimental evidence for RNA modification in EBER1. Thus, we also propose to uncover the factors involved in depositing and interpreting this modification to study the significance of RNA modification in EBER1 for the EBV life cycle. In summary, we expect that the proposed investigations will yield significant insights into how EBER1 contributes to viral replication and thus tumor development. In light of the fact that EBER1 by itself harbors oncogenic properties, our proposed studies may indicate viable therapeutic avenues for targeting the cancer- causing potential of EBV.