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:
- 金额:$ 31.54万
- 依托单位:
- 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:
- 关键词:ATM Signaling PathwayATM activationAffectAnal carcinomaAntiviral AgentsAtaxia-Telangiectasia-Mutated protein kinaseCancer EtiologyCell CycleCell Cycle DeregulationCellsChromatin ModelingCountryDNADNA DamageDNA Double Strand BreakDNA RepairDNA Repair PathwayDNA Replication DamageDevelopmentDiseaseDouble Strand Break RepairE2F1 geneEnsureEpisomeEpitheliumGene ExpressionGenerationsGenomeGenome StabilityGenomic InstabilityGoalsHPV-High RiskHead and Neck CancerHealthHistonesHumanHuman PapillomavirusHuman papilloma virus infectionInfectionInfection preventionKnowledgeLife Cycle StagesLinkMaintenanceMalignant NeoplasmsMalignant neoplasm of cervix uteriMediatingNucleosomesPathway interactionsPhasePhosphorylationPrevalenceProductionProteinsRecruitment ActivityRegulationReporterSignal PathwayStat5 proteinStressTestingUndifferentiatedVaccinesVariantViralViral GenomeViral PathogenesisVirionWomanWorkcancer preventioncarcinogenesishomologous recombinationinsightnovelprophylacticrecombinational repairrepairedresponsetherapeutic developmenttherapeutic targettranscription factorviral 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。
项目成果
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{{ truncateString('CARY A MOODY', 18)}}的其他基金
Interplay between the cellular DNA damage response and the HPV life cycle
细胞 DNA 损伤反应与 HPV 生命周期之间的相互作用
- 批准号:
10734394 - 财政年份:2023
- 资助金额:
$ 31.54万 - 项目类别:
Regulation of DNA Damage and Innate Immunity During the Productive Phase of the HPV Life Cycle
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10392849 - 财政年份:2021
- 资助金额:
$ 31.54万 - 项目类别:
Epigenetic Regulation During the HPV Life Cycle
HPV 生命周期中的表观遗传调控
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10295782 - 财政年份:2018
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Epigenetic Regulation During the HPV Life Cycle
HPV 生命周期中的表观遗传调控
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10053334 - 财政年份:2018
- 资助金额:
$ 31.54万 - 项目类别:
Epigenetic Regulation During the HPV Life Cycle
HPV 生命周期中的表观遗传调控
- 批准号:
10520010 - 财政年份:2018
- 资助金额:
$ 31.54万 - 项目类别:
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:
9325478 - 财政年份:2014
- 资助金额:
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Regulation of human papillomavirus replication by the DNA damage response
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8759078 - 财政年份:2014
- 资助金额:
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The Role of Caspase Activation in the Differentiation-Dependent Life Cycle of HPV
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- 批准号:
7574657 - 财政年份:2008
- 资助金额:
$ 31.54万 - 项目类别:
The Role of Caspase Activation in the Differentiation-Dependent Life Cycle of HPV
Caspase 激活在 HPV 分化依赖性生命周期中的作用
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8122505 - 财政年份:2008
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$ 31.54万 - 项目类别:
The Role of Caspase Activation in the Differentiation-Dependent Life Cycle of HPV
Caspase 激活在 HPV 分化依赖性生命周期中的作用
- 批准号:
8307447 - 财政年份:2008
- 资助金额:
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