HPV and the DNA Damage Response

HPV 和 DNA 损伤反应

• 批准号: 8270643
• 负责人: Laimonis A. LAIMINS
• 金额: $ 30.69万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8270643
• 关键词: ATM Signaling Pathway; Area; Basal Cell; Binding; Caspase; Cause of Death; Cells; DNA Damage; Episome; Epithelial Cells; FDA approved; Genome; Goals; Human Papilloma Virus Vaccine; Human Papillomavirus; Human papilloma virus infection; Infection; Lesion; Link; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Pathway interactions; Play; Proteins; Role; Survival Rate; Undifferentiated; Vaccines; Viral; Virion; Woman; Work; base; inhibitor/antagonist; member; prophylactic; response

DESCRIPTION (provided by applicant): The long-term goal of our studies is to determine the mechanisms by which human papillomaviruses regulate productive replication in differentiating epithelial cells. During productive infection, HPV genomes are stably maintained as low copy episomes in undifferentiated basal cells, while genome amplification and virion assembly occur in highly differentiated suprabasal cells. Our recent work has demonstrated that HPV proteins activate the ATM DNA damage response and that this is necessary for genome amplification in differentiating cells. Interestingly only a subset of ATM pathway members are activated by HPV proteins upon differentiation. Further studies indicate that E7 binds to ATM and this may be responsible for activating a subset of ATM pathway members. We have also demonstrated that HPV proteins also induce low levels of caspase cleavage upon differentiation and that this is also necessary for productive replication in differentiating cells. The ATM pathway appears to be linked to caspase activation as inhibitors of Chk2 block caspase cleavage. These observations form the basis of the proposed studies to examine the role that DNA damage pathways play in HPV amplification in differentiating cells. In this application we will ask the following questions: 1: Which members of the ATM pathway play essential roles for productive viral replication in differentiating cells? Why is ATM pathway important for amplification in differentiating cells? 2). How does E7 contribute to activation of the ATM pathway? Could other HPV proteins play a role? 3). What role does the ATM pathway play in differentiation-induced activation of caspases? How does E7 activate this pathway?

描述（由申请人提供）：我们研究的长期目标是确定人乳头瘤病毒在分化上皮细胞中调节有效复制的机制。在生产性感染期间，HPV基因组在未分化的基底细胞中以低拷贝附加体的形式稳定维持，而基因组扩增和病毒粒子组装发生在高度分化的基底细胞中。我们最近的工作表明，HPV 蛋白激活 ATM DNA 损伤反应，这对于分化细胞中的基因组扩增是必要的。有趣的是，只有 ATM 通路成员的一个子集在分化时被 HPV 蛋白激活。进一步的研究表明 E7 与 ATM 结合，这可能负责激活 ATM 通路成员的子集。我们还证明，HPV 蛋白还在分化时诱导低水平的半胱天冬酶裂解，这对于分化细胞中的有效复制也是必要的。 ATM 通路似乎与 caspase 激活有关，因为 Chk2 抑制剂会阻止 caspase 裂解。这些观察结果构成了拟议研究的基础，以检查 DNA 损伤途径在分化细胞中 HPV 扩增中所起的作用。在此应用中，我们将提出以下问题： 1：ATM 途径的哪些成员对于分化细胞中的高效病毒复制发挥重要作用？为什么 ATM 通路对于分化细胞的扩增很重要？ 2）。 E7 如何促进 ATM 通路的激活？其他 HPV 蛋白会发挥作用吗？ 3）。 ATM 通路在分化诱导的 caspase 激活中发挥什么作用？ E7如何激活这条通路？