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Functions of EBNA1 in replication & partitioning of EBV

EBNA1 在复制中的功能

基本信息

批准号：
7846932
负责人：
Ashok A Aiyar
金额：
$ 0.97万
依托单位：
LSU HEALTH SCIENCES CENTER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-01 至 2010-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Epstein-Barr virus (EBV) is a human herpesvirus that causes infectious mononucleosis. Prospective epidemiologic studies indicate that EBV is causally associated with at least two malignancies - endemic Burkitt's lymphoma, and nasopharyngeal carcinoma. EBV's genome is latent in all these diseases, and is maintained as a nuclear episome that replicates once per cell cycle, and is efficiently partitioned at mitosis. Understanding the mechanism by which EBV episomes are replicated once per cell-cycle and partitioned will ultimately yield therapies against all diseases caused by a latent EBV infection. The long-range goal of these studies is to understand how viral episomes in general, but EBV genomes in specific, are maintained in a functional state with the capacity to cause human disease. The only viral protein that is required for EBV genome maintenance and partitioning is the Epstein-Barr nuclear antigen 1 (EBNA1), which binds a viral cis-element termed oriP through its carboxy-terminal DNA-binding domain. OriP contains two sets of binding sites for EBNA1 - DS, a region that serves as an origin of replication, and FR, a region that serves as an episome maintenance and partitioning element when EBNA1 is bound to it. We have recently discovered that the amino-terminal domain of EBNA1 has two regions within it that are AT-hooks, corresponding to the AT-hooks of cellular proteins such as the prototypic AT-hook protein HMGA1a. Confirming this observation, we have demonstrated that we can functionally replace the N-terminus of EBNA1 with the AT-hooks of HMGA1a. In this proposal we propose to extend our studies in three areas: 1. To characterize the roles of the AT-hook regions of EBNA1 in chromosome tethering and episome maintenance. 2. To utilize a novel replicon and fusion protein to understand the function of EBNA1 in replication. 3. To use viral genetics to determine the functions of EBNA1 in the immortalization of naive B-cells by EBV

描述（由申请人提供）：EB病毒（EBV）是一种引起传染性单核细胞增多症的人类疱疹病毒。前瞻性流行病学研究表明，EBV 与至少两种恶性肿瘤（地方性伯基特淋巴瘤和鼻咽癌）存在因果关系。 EBV 的基因组潜伏在所有这些疾病中，并以核附加体的形式维持，每个细胞周期复制一次，并在有丝分裂时有效分配。了解 EBV 附加体在每个细胞周期复制一次并分配的机制将最终产生针对潜伏 EBV 感染引起的所有疾病的治疗方法。这些研究的长期目标是了解一般病毒附加体（特别是 EBV 基因组）如何保持功能状态，并具有导致人类疾病的能力。 EBV 基因组维持和分区所需的唯一病毒蛋白是 Epstein-Barr 核抗原 1 (EBNA1)，它通过其羧基末端 DNA 结合域结合称为 oriP 的病毒顺式元件。 OriP 包含两组 EBNA1 结合位点 - DS（充当复制起点的区域）和 FR（当 EBNA1 与其结合时充当附加体维持和分配元件的区域）。我们最近发现EBNA1的氨基末端结构域内有两个AT钩子区域，对应于细胞蛋白的AT钩子，例如原型AT钩子蛋白HMGA1a。证实了这一观察结果，我们证明我们可以在功能上用 HMGA1a 的 AT 钩替换 EBNA1 的 N 末端。在本提案中，我们建议在三个领域扩展我们的研究： 1. 描述 EBNA1 的 AT 钩子区域在染色体束缚和附加体维持中的作用。 2. 利用新型复制子和融合蛋白来了解EBNA1在复制中的功能。 3. 利用病毒遗传学确定 EBNA1 在 EBV 使幼稚 B 细胞永生化中的功能