Regulation of human papillomavirus replication by the DNA damage response

DNA损伤反应调节人乳头瘤病毒复制

基本信息

批准号：
9325478
负责人：
CARY A MOODY
金额：
$ 31.54万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-11 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9325478
关键词：
ATM Signaling Pathway ATM activation Affect Anal carcinoma Antiviral Agents Cancer Etiology Cell Cycle Cell Cycle Deregulation Cell Differentiation process Cells Chromatin Modeling Clinical Treatment Country DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Pathway DNA Replication Damage Development Disease Double Strand Break Repair E2F1 gene Ensure Episome Epithelium Gene Expression Generations Genome Genome Stability Genomic Instability Goals HPV-High Risk Head and Neck Cancer Histones Human Human Papillomavirus Human papilloma virus infection Infection Infection prevention Knowledge Life Cycle Stages Link Maintenance Malignant Neoplasms Malignant neoplasm of cervix uteri Mediating Nucleosomes Pathway interactions Phase Phosphorylation Prevalence Preventive vaccine Production Proteins Recruitment Activity Regulation Reporter Signal Pathway Stat5 protein Stress Testing Undifferentiated Variant Viral Viral Genome Viral Pathogenesis Virion Virus Assembly Virus Replication Woman Work ataxia telangiectasia mutated protein cancer prevention carcinogenesis ds-DNA homologous recombination insight novel public health relevance recombinational repair repaired response therapeutic development transcription factor viral DNA

项目摘要

DESCRIPTION (provided by applicant): The productive phase of the HPV life cycle is restricted to the uppermost layer of the epithelium, in cells that have normally exited the cell cycle. The E7 protein maintains differentiating cells active in the cell cycle, allowing for productive replication and virion production. Cell cycle deregulation by E7 results in genomic instability that contributes to cancer development. Our long-term goal is to identify mechanisms that regulate the productive phase of the viral life cycle, which is important to understanding how HPV causes cancer. This proposal focuses on determining how HPV commandeers the ATM DNA damage-signaling pathway to facilitate productive replication. We will identify the mechanisms by which HPV activates ATM and determine how HPV utilizes ATM activity to drive viral replication. We hypothesize that HPV highjacks DNA signaling pathways through E7, leading to ATM activation that drives productive replication through homologous recombination repair. Specific Aims to test this are: (1) To determine how HPV causes DNA damage by determining the contribution of E2F and STAT5 transcription factors to E7-induced ATM signaling. (2) To determine if ATM activity alters viral assembly of chromatin to facilitate DNA repair factor recruitment, as well as the contribution of the histone variant H2AX to viral replication. (3) To determine how DNA double strand break (DSB) repair pathways are regulated in HPV infected cells by using chromosomally integrated reporters for distinct repair pathways. We will also determine the contribution of the ATM target Nbs1, and the homologous recombination repair factors Rad51 and Brca1, to viral replication. Since ATM is essential to the maintenance of genomic stability and the prevention of cancer, it is important to understand how HPV manipulates this pathway to ensure completion of the viral life cycle. These studies will provide insight not only into viral life cycle, but also the potential mechanisms by which HPV induces genomic instability.

描述（由申请人提供）：HPV 生命周期的产生阶段仅限于正常退出细胞周期的细胞的上皮最上层。 E7 蛋白使分化细胞在细胞周期中保持活跃，从而实现高效复制和病毒粒子生产。 E7 导致细胞周期失调导致基因组不稳定，从而促进癌症的发展。我们的长期目标是确定调节病毒生命周期生产阶段的机制，这对于理解如何调节病毒生命周期的生产阶段非常重要。 HPV 会导致癌症。该提案的重点是确定 HPV 如何控制 ATM DNA 损伤信号通路以促进高效复制。我们将确定 HPV 激活 ATM 的机制，并确定 HPV 如何利用 ATM 活性来驱动病毒复制。我们假设 HPV 通过 E7 劫持 DNA 信号通路，导致 ATM 激活，通过同源重组修复驱动高效复制。测试这一点的具体目的是： (1) 通过确定 E2F 和 STAT5 转录因子对 E7 诱导的 ATM 信号传导的贡献来确定 HPV 如何引起 DNA 损伤。 (2) 确定 ATM 活性是否改变病毒染色质组装以促进 DNA 修复因子的招募，以及组蛋白变体 H2AX 对病毒复制的贡献。 (3) 确定如何通过使用染色体整合报告基因来调节不同修复途径的 HPV 感染细胞中的 DNA 双链断裂 (DSB) 修复途径。我们还将确定 ATM 靶标 Nbs1 以及同源重组修复因子 Rad51 和 Brca1 对病毒复制的贡献。由于 ATM 对于维持基因组稳定性和预防癌症至关重要，因此了解 HPV 如何操纵该途径以确保完成病毒生命周期非常重要。这些研究不仅将提供对病毒生命周期的深入了解，而且还将提供 HPV 诱导基因组不稳定的潜在机制。