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

• 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
• 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

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生命周期的产生期仅限于正常退出细胞周期的细胞的上皮最上层。E7蛋白维持分化细胞在细胞周期中的活跃状态，允许有效的复制和病毒粒子的产生。E7对细胞周期的失控会导致基因组不稳定，从而导致癌症的发展。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 人乳头瘤病毒会致癌。这项建议的重点是确定HPV如何侵占ATM DNA损伤信号通路，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生产性复制。具体目的是：(1)通过确定E2F和STAT5转录因子在E7诱导的ATM信号中的作用，确定HPV如何导致DNA损伤。(2)确定ATM活性是否改变了病毒染色质的组装以促进DNA修复因子的募集，以及组蛋白变异体H2AX对病毒复制的贡献。(3)利用不同修复途径的染色体整合报告基因，研究DNA双链断裂(DSB)修复途径在HPV感染细胞中的调控作用。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如何操纵这一途径以确保病毒生命周期的完成是很重要的。这些研究将不仅提供对病毒生命周期的洞察，而且还将提供关于HPV导致基因组不稳定的潜在机制的见解。