Epigenetic Regulation During the HPV Life Cycle

HPV 生命周期中的表观遗传调控

基本信息

  • 批准号:
    10520010
  • 负责人:
  • 金额:
    $ 34.86万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-12-06 至 2024-11-30
  • 项目状态:
    已结题

项目摘要

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 alters cell cycle regulation to push differentiating cells back into the cell cycle, allowing for productive replication and virion production. Cell cycle deregulation by E7 leads to genomic instability that is a driving force in cancer development. Our long-term goal is to understand mechanisms that regulate productive viral replication, which is important to understanding how HPV causes cancer. HPV genomes are histone-associated, though the impact of histone post-translational modifications on the viral life cycle is unclear. This proposal focuses on understanding how HPV utilizes the SETD2 methyltransferase to facilitate viral replication. SETD2 adds the trimethyl mark to histone H3 on lysine 36 (H3K36me3) during transcription elongation and regulates multiple cellular processes through the recruitment of numerous effector proteins to H3K36me3. We will identify the mechanisms by which SETD2 activity contributes to viral replication and determine how E7 increases the stability of SETD2. We hypothesize that HPV epigenetically regulates the viral life cycle through SETD2-mediated H3K36me3 on viral, as well as cellular chromatin. Specific Aims to test this are: (1) To determine the mechanism by which SETD2 facilitates viral replication by examining whether SETD2 knockdown affects transcription, RNA processing and DNA repair on viral genomes, as well as by identifying H3K36me3 readers bound to HPV DNA. (2) To determine the mechanism by which E7 increases the protein stability of SETD2 by examining known modulators of SETD2 stability, as well as by identifying SETD2 interacting partners though a non-biased approach using a BirA- tagged SETD2 coupled with mass spectrometry. Since SETD2 is essential to the maintenance of genomic stability, it is important to understand how HPV utilizes this epigenetic modifier to facilitate viral replication. Understanding how SETD2 activity promotes the viral life cycle will provide insight into mechanisms of viral persistence, as well as genomic instability. These studies may also identify therapeutic targets for the treatment of HPV-associated diseases.
HPV生命周期的产生期被限制在最上层的上皮,在正常情况下已经退出细胞周期的细胞中。E7蛋白改变细胞周期调节,将分化的细胞推回到细胞周期,从而实现高效复制和病毒粒子的产生。E7对细胞周期的失控导致基因组不稳定,而基因组不稳定是癌症发展的驱动力。我们的长期目标是了解调节病毒复制的机制,这对了解HPV如何导致癌症很重要。HPV基因组与组蛋白相关,尽管组蛋白翻译后修饰对病毒生命周期的影响尚不清楚。这项建议的重点是了解HPV如何利用SETD2甲基转移酶来促进病毒复制。在转录延伸过程中,SETD2将三甲基标记添加到赖氨酸36(H3K36me3)上的组蛋白H3上,并通过向H3K36me3募集大量效应蛋白来调节多种细胞过程。我们将确定SETD2活性促进病毒复制的机制,并确定E7如何增加SETD2的稳定性。我们假设HPV通过SETD2介导的病毒上的H3K36me3以及细胞染色质在表观上调节病毒的生命周期。具体目的是:(1)通过检测SETD2敲除是否影响病毒基因组上的转录、RNA处理和DNA修复,以及通过鉴定与HPV DNA结合的H3K36me3读取器,来确定SETD2促进病毒复制的机制。(2)通过检测已知的SETD2稳定性调节因子,以及通过使用BIRA标记的SETD2结合质谱仪的无偏方法识别SETD2相互作用伙伴,来确定E7增加SETD2蛋白质稳定性的机制。由于SETD2对于维持基因组稳定性是必不可少的,因此了解HPV如何利用这种表观遗传修饰来促进病毒复制是很重要的。了解SETD2活性如何促进病毒生命周期,将有助于深入了解病毒持续存在的机制,以及基因组的不稳定性。这些研究还可能确定治疗HPV相关疾病的靶点。

项目成果

期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
SETD2-dependent H3K36me3 plays a critical role in epigenetic regulation of the HPV31 life cycle.
  • DOI:
    10.1371/journal.ppat.1007367
  • 发表时间:
    2018-10
  • 期刊:
  • 影响因子:
    6.7
  • 作者:
    Gautam D;Johnson BA;Mac M;Moody CA
  • 通讯作者:
    Moody CA
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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:
    $ 34.86万
  • 项目类别:
Regulation of DNA Damage and Innate Immunity During the Productive Phase of the HPV Life Cycle
HPV 生命周期生产阶段 DNA 损伤和先天免疫的调节
  • 批准号:
    10392849
  • 财政年份:
    2021
  • 资助金额:
    $ 34.86万
  • 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:
    10295782
  • 财政年份:
    2018
  • 资助金额:
    $ 34.86万
  • 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:
    10053334
  • 财政年份:
    2018
  • 资助金额:
    $ 34.86万
  • 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:
    $ 34.86万
  • 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:
    8926368
  • 财政年份:
    2014
  • 资助金额:
    $ 34.86万
  • 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:
    8759078
  • 财政年份:
    2014
  • 资助金额:
    $ 34.86万
  • 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:
    7574657
  • 财政年份:
    2008
  • 资助金额:
    $ 34.86万
  • 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:
    8122505
  • 财政年份:
    2008
  • 资助金额:
    $ 34.86万
  • 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:
    $ 34.86万
  • 项目类别:

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