Cytomegalovirus and Nuclear Tumor Suppressors

描述（由申请人提供）：我的长期目标是了解细胞核中的调节功能与人类巨细胞病毒（HCMV）和其他DNA病毒的复制之间的关系。本项目研究宿主对HCMV感染的“基因组应激”反应，特别是细胞DNA损伤反应，以及这种反应如何影响HCMV复制。众所周知，HCMV感染的细胞导致p53应答，其功能显然受到IE2结合的阻碍。然而，导致初始宿主试图激活p53的事件尚不清楚。我们发现由共济失调毛细血管扩张突变（Atm）基因编码的激酶在感染期间被激活并磷酸化p53。Atm通常在DNA损伤等基因组压力下被激活。一旦激活，Atm信号增殖检查点和刺激DNA修复/重组功能。鉴于这些与Atm信号相关的深刻影响，我假设负责Atm激活和随后信号传导的事件影响HCMV复制的能力。与激活的Atm通常在阻断DNA合成中所起的作用相反，我们的初步结果表明，Atm是最佳HCMV复制所必需的。因此，HCMV似乎激活了细胞中的核应激反应，然后利用它来促进病毒复制。在本应用程序中，我建议确定Atm如何激活及其在调节HCMV复制中的作用，并确定负责Atm激活的事件并确定它们在HCMV复制中的作用。

DESCRIPTION (provided by applicant): My long-term goal is to understand the relationship between regulatory functions in the nucleus and the replication of human cytomegalovirus (HCMV) and other DNA viruses. This project examines the host response to HCMV infection relating to "genomic stress", in particular the cellular DNA damage response, and how this response affects HCMV replication. It is known that HCMV infected cells result in a p53 response, whose function is apparently thwarted by IE2 binding. However, the event(s) that leads to the initial host attempt to activate p53 are not understood. We find that the kinase encoded by the ataxia telangiectasia mutated (Atm) gene is activated and phosphorylates p53 during infection. Atm is usually activated in response to genomic stresses such as DNA damage. Once activated, Atm signals proliferation checkpoints and stimulates DNA repair/recombination functions. Given these profound effects associated with Atm signaling, I hypothesize that the event(s) responsible for Atm activation and subsequent signaling affect the ability of HCMV to replicate. Contrary to the role activated Atm normally plays in blocking DNA synthesis, our preliminary results suggest that Atm is required for optimal HCMV replication. Thus it appears that HCMV activates a nuclear stress response in cells and then uses it to facilitate virus replication. In this application, I propose to determine how Atm is activated and its role in modulating HCMV replication, and to identify the event(s) responsible for Atm activation and determine their role in HCMV replication. A result of this research will be the identification of new potential targets for the treatment of cytomegalovirus infections. Future work will determine whether other viruses active and require the same pathways for replication and possibly expand the list of viruses that might be inhibited by targeting these pathways.