Regulation of EBV reactivation

描述（由申请方提供）：EB病毒（EBV）是一种致癌性人类疱疹病毒，与淋巴和上皮恶性肿瘤有关。EBV的传播和致病依赖于病毒裂解周期的有效激活。EBV裂解周期的主要起始物是立即早期蛋白Zta（也称为ZEBRA、BZLF 1和EB 1）。Zta是DNA结合蛋白的碱性亮氨酸拉链（b-zip）家族的非典型成员，与细胞C/EBP家族具有序列相似性，与卡波西肉瘤相关疱疹病毒（KSHV）K8蛋白具有功能同源性。Zta可以与病毒和细胞基因组中的多个序列元件结合，以刺激转录活性和起源特异性DNA复制。Zta还可以窃取宿主因子，从而为病毒复制创造一个宽松的环境。Zta结合裂解周期DNA复制的病毒起点（OriLyt）并使病毒复制体成核的能力表明其是EBV起点结合蛋白（OBP），并且可能与α和β疱疹病毒OBP UL 9共享特性。新的初步数据表明，Zta具有单链DNA结合活性，并可以识别在OriLyt的基本上游元件处形成的DNA发夹。与UL 9一样，Zta具有高度保守且氧化还原敏感的半胱氨酸残基，其对于复制功能和单链DNA结合是必需的。氧化还原敏感的半胱氨酸也是激活C/EBP 2所必需的，C/EBP 2是一种使KSHV裂解源复制体成核的细胞因子。在这个应用中，我们提出了调查的生物化学，调节，和基因组生物学Zta在EBV裂解复制的再激活。我们将测试的总体假设，Zta与其他疱疹病毒OBP共享生化和功能特性，这些共同的属性是必不可少的调节和启动裂解复制。

DESCRIPTION (provided by applicant): Epstein-Barr virus (EBV) is an oncogenic human herpesvirus that has been linked to lymphoid and epithelial malignancies. The propagation and pathogenesis of EBV depends on the efficient activation of the viral lytic cycle. The primary initiator of the EBV lytic cycle is the immediate early protein Zta (also referred to as ZEBRA, BZLF1, and EB1). Zta is an atypical member of the basic-leuzine zipper (b-zip) family of DNA binding proteins with sequence similarity to the cellular C/EBP family, and functional homology with the Kaposi's Sarcoma Associated Herpesvirus (KSHV) K8 protein. Zta can bind to multiple sequence elements in the viral and cellular genome to stimulate transcription activity and origin-specific DNA replication. Zta can also pirate host factors necessary to create a permissive environment for viral replication. The ability of Zta to bind the viral origin of lytic cycle DNA replication (OriLyt) and nucleate a viral replisome suggests that is the EBV origin binding protein (OBP), and likely to share properties with the alpha and beta herpesvirus OBP UL9. New preliminary data indicates that Zta possesses single stranded DNA binding activity and can recognize a DNA hairpin that forms at the essential upstream element of OriLyt. Zta, like UL9, have a highly conserved and redox sensitive cysteine residue that is essential for replication function and single strand DNA binding. A redox sensitive cysteine is also essential for activation of C/EBP 2, a cellular factor that nucleates the KSHV lytic origin replisome. In this application, we propose to investigate the biochemistry, regulation, and genome biology of Zta in the reactivation of EBV lytic replication. We will test the overarching hypothesis that Zta shares biochemical and functional properties with other herpesvirus OBPs and that these common properties are essential for regulation and initiation of lytic replication.