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：
8926368
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/8926368
关键词：
ATM Signaling Pathway ATM activation Affect Anal carcinoma Antiviral Agents Ataxia-Telangiectasia-Mutated protein kinase Cancer Etiology Cell Cycle Cell Cycle Deregulation Cells Chromatin Modeling 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 Health 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 Production Proteins Recruitment Activity Regulation Reporter Signal Pathway Stat5 protein Stress Testing Undifferentiated Vaccines Variant Viral Viral Genome Viral Pathogenesis Virion Woman Work cancer prevention carcinogenesis homologous recombination insight novel prophylactic recombinational repair repaired response therapeutic development therapeutic target 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生命周期的生产阶段仅限于通常退出细胞周期的细胞中上皮的最上层。 E7蛋白在细胞周期中保持分化的细胞，从而使生产性复制和病毒体产生。 E7细胞周期放松管制会导致基因组不稳定性，这有助于癌症的发展。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，这对于了解如何理解如何了解 HPV引起癌症。该建议重点是确定HPV如何指挥ATM DNA损伤信号途径以促进生产性复制。我们将确定HPV激活ATM的机制，并确定HPV如何利用ATM活动来驱动病毒复制。我们假设HPV HighJacks通过E7通过E7的DNA信号通路，导致ATM激活，通过同源重组修复来驱动生产性复制。测试目的的具体目的是：（1）确定HPV如何通过确定E2F和STAT5转录因子对E7诱导的ATM信号的贡献来导致DNA损伤。（2）确定ATM活性是否改变了染色质的病毒组装以促进DNA修复因子募集，以及组蛋白变体H2AX对病毒复制的贡献。（3）通过使用染色体集成的记者进行不同的修复途径来确定在HPV感染细胞中如何调节DNA双链（DSB）修复途径。我们还将确定ATM目标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，因此重要的是要了解HPV如何操纵这一途径以确保病毒生命周期的完成。这些研究将不仅提供对病毒生命周期的见识，还将提供HPV诱导基因组不稳定性的潜在机制。