Characterizing the Molecular Mode of Action of EBV Noncoding RNA EBER1

项目总结 爱泼斯坦-巴尔病毒(EBV)是第一个发现的人类致癌病毒。EBV主要感染 淋巴细胞和上皮细胞，可分别导致多种淋巴瘤和癌症。 世界上超过90%的人口感染了这种病毒，但在健康人群中，感染大多是无症状的 个人。EBV的致癌潜力变得显而易见，特别是在免疫功能低下的患者 个人，例如长期接受免疫抑制治疗的移植受者 药物治疗，在这种情况下，病毒的重新激活可以推动肿瘤的形成。 除了病毒蛋白外，EBV还表达两个高度丰富的非编码RNA，称为EBER1和EBER2。 这两种非编码RNA都表现出严格的核定位，并且与其他RNA一样在高水平上表达 非常丰富的宿主非编码RNA，执行重要的细胞功能。在此基础上可以假定。 高拷贝数以及在EBV执行的所有临床分离株中都发现EBV的事实 或在感染过程中干扰重要的细胞过程。虽然我们在阐明 EBER2促进EBV生命周期的分子机制--EBER1的分子功能 仍然是个谜。鉴于EBER1和EBER2之间的巨大相似之处，我们假设EBER1 也可以执行与EBER2类似的功能，即与染色质上的特定位点结合并调节基因 表情。在这里，我们建议应用尖端技术结合适体技术和下一步- 世代测序，以进一步了解EBER1的分子机制。此外，我们还拥有 最近获得了EBER1中RNA修饰的实验证据。因此，我们还建议揭开 储存和解释这一修饰的因素对研究RNA的意义 EBER1中针对EBV生命周期的修改。 总而言之，我们预计拟议的调查将对EBER1如何 有助于病毒复制，从而促进肿瘤的发展。鉴于EBER1本身蕴藏着 致癌特性，我们建议的研究可能会为靶向癌症的可行治疗途径- 可能会引发EB病毒。

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.