Cytomegalovirus and Nuclear Tumor Suppressors

巨细胞病毒和核肿瘤抑制因子

• 批准号: 7898886
• 负责人: TIMOTHY F KOWALIK
• 金额: $ 39.45万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7898886
• 关键词: ATM gene; ATM wt Allele; Affect; Binding; Biological Assay; CDC25A gene; CHEK2 gene; Cell Nucleus; Cells; Cytomegalovirus; Cytomegalovirus Infections; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Pathway; DNA Replication Damage; DNA Viruses; DNA biosynthesis; Dominant-Negative Mutation; Event; Fibroblasts; Future; Gene Expression; Genes; Genetic Recombination; Genomics; Goals; Immune response; Infection; Nonhomologous DNA End Joining; Nuclear; Pathway interactions; Phosphotransferases; Play; Reactive Oxygen Species; Research; Research Personnel; Role; Signal Pathway; Signal Transduction; Stress; TP53 gene; Tumor Suppressor Proteins; Virus; Virus Diseases; Virus Replication; Work; ataxia telangiectasia mutated protein; biological adaptation to stress; homologous recombination; inhibitor/antagonist; response

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.

描述（由申请人提供）：我的长期目标是了解细胞核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。该项目检查宿主对与“基因组应激”相关的 HCMV 感染的反应，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 感染的细胞会产生 p53 反应，但 IE2 结合显然会阻碍其功能。然而，导致宿主最初尝试激活 p53 的事件尚不清楚。我们发现共济失调毛细血管扩张突变 (Atm) 基因编码的激酶在感染过程中被激活并使 p53 磷酸化。 Atm 通常会因 DNA 损伤等基因组应激而被激活。一旦被激活，Atm 就会向增殖检查点发出信号并刺激 DNA 修复/重组功能。鉴于与 Atm 信号传导相关的这些深远影响，我假设负责 Atm 激活和后续信号传导的事件会影响 HCMV 的复制能力。与激活的 Atm 通常在阻断 DNA 合成中发挥的作用相反，我们的初步结果表明 Atm 是最佳 HCMV 复制所必需的。因此，HCMV 似乎激活细胞中的核应激反应，然后利用它来促进病毒复制。在此应用中，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。 这项研究的结果将是确定治疗巨细胞病毒感染的新的潜在靶标。未来的工作将确定其他病毒是否活跃并需要相同的复制途径，并可能扩大通过针对这些途径而可能被抑制的病毒列表。