HPV and the DNA Damage Response

HPV 和 DNA 损伤反应

• 批准号: 8677767
• 负责人: Laimonis A. LAIMINS
• 金额: $ 29.77万
• 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 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8677767
• 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调节分化上皮细胞中生产性复制的机制。在生产性感染过程中，HPV基因组在未分化的基底细胞中稳定地保持为低拷贝偶发，而基因组扩增和病毒粒子组装出现在高度分化的上超质细胞中。我们最近的工作表明，HPV蛋白激活了ATM DNA损伤反应，这对于分化细胞中的基因组扩增是必不可少的。有趣的是，只有ATM途径成员的一部分被HPV蛋白在分化时被激活。进一步的研究表明，E7与ATM结合，这可能负责激活ATM途径成员的子集。我们还证明，HPV蛋白还会在分化时诱导低水平的caspase裂解，这对于分化细胞中的生产性复制也是必要的。 ATM途径似乎与CASPase激活有关，作为CHK2阻止caspase裂解的抑制剂。这些观察结果构成了拟议的研究的基础，以研究DNA损伤途径在分化细胞中HPV扩增中起的作用。在此应用程序中，我们将提出以下问题：1：ATM途径的哪些成员在分化细胞中的生产性病毒复制起着重要作用？为什么ATM途径对于分化细胞的扩增至关重要？ 2）。 E7如何促进ATM途径的激活？其他HPV蛋白可以发挥作用吗？ 3）。 ATM途径在分化引起的胱天蛋白酶激活中起什么作用？ E7如何激活这一途径？