Renewal: HPV and the DNA Damage Response

更新:HPV 和 DNA 损伤反应

基本信息

项目摘要

Human papillomaviruses (HPV) are the causative agents of cervical, anal and many oral cancers. While prophylactic vaccines have been developed to prevent HPV infections, there is no effective therapeutic treatment for existing HPV lesions. It is therefore of critical importance to understand how the productive life cycle of high- risk HPVs is regulated to identify potential new therapeutic targets. HPVs infect stratified squamous epithelia and link their productive life cycles to the differentiation of the infected cell. My laboratory demonstrated that the amplification of HPV genomes in differentiating cells is dependent on activation of two DNA damage repair (DDR) pathways: the ataxia-telangiectasia mutated (ATM) kinase pathway as well as the ataxia telangiectasia and Rad3-related (ATR) pathway. We have identified members of these pathways that are important for the HPV life cycle and characterized many critical activities. We determined that in HPV positive cells the ATR binding protein, TopBP1, activated expression of DNA damage repair factors along with p73 while additional ATR factors, p62/GATA4, controlled expression of cytokines as well as IFNκ. Further work demonstrated that HPV proteins induced high rates of DNA breaks in both cellular and viral DNAs. The breaks in viral genomes were shown to be rapidly repaired through the preferential recruitment of homologous recombination repair factors such as RAD51 and BRCA1 to episomes and away from cellular sites of damage. This preferential repair resulted in genome amplification while at the same time permitting accumulation of breaks in cellular loci. The topoisomerase TOP2β induces DNA breaks to relieve torsional stress caused by transcription and replication. We determined that TOP2β levels were substantially increased in HPV positive cells and that this was responsible for the generation of a majority of breaks in HPV positive cells. Importantly knockdown of TOP2β impaired activation of DDR pathways and blocked viral replication. Additional work showed that HPV positive cells contain enhanced levels of R-loops which are trimeric complexes of RNA and DNA that lead to stalled replication forks and DNA breaks. R-loops were detected on HPV genomes in undifferentiated cells but resolved upon differentiation suggesting they may help in regulating viral functions. In this application, we will investigate how ATR regulates the stable maintenance of viral episomes in undifferentiated cells along with what determines which cells that undergo amplification upon differentiation. Additional work will examine which DDR and replication factors associate with amplifying genomes and how these pathways are activated. The overall goal of our studies is to understand how members of the DNA damage repair pathways regulate the differentiation- dependent HPV life cycle.
人乳头瘤病毒(HPV)是宫颈,肛门和许多口服癌的灾难性药物。虽然已经开发了预防性疫苗来预防HPV感染,但现有的HPV病变尚无有效的治疗治疗。因此,重要的是要了解高风险HPV的生产生命周期以确定潜在的新治疗靶标。 HPV感染了分层的鳞状上皮,并将其生产寿命与感染细胞的分化联系起来。我的实验室证明,分化细胞中HPV基因组的扩增取决于两种DNA损伤修复(DDR)途径的激活:thaxia telangiotapasia突变(ATT)激酶途径以及teLangiectiia telangiectasia and rad3相关(ATR3)途径。我们已经确定了这些途径的成员,这些成员对于HPV生命周期很重要,并表征了许多关键活动。我们确定在HPV阳性细胞中,ATR结合蛋白TOPBP1与p73一起激活了DNA损伤修复因子的表达,而其他ATR因子P62/GATA4则控制了细胞因子和IFNκ的表达。进一步的工作表明,HPV蛋白在细胞和病毒DNA中诱导高率DNA断裂率。通过首选募集同源重组修复因子(例如RAD51和BRCA1)到插发事件,并远离损害的细胞部位,病毒基因组中的断裂被证明可以迅速修复。这种首选修复会导致基因组扩增,同时允许在细胞基因座中断裂的加速。拓扑异构酶TOP2β诱导DNA断裂,以减轻转录和复制引起的扭转应激。我们确定HPV阳性细胞中TOP2β水平大大升高,这是导致HPV阳性细胞中大部分断裂产生的原因。重要的是,敲低DDR途径激活和病毒复制的激活受损。其他工作表明,HPV阳性细胞含有增强水平的R-loops,这是RNA和DNA的三聚体复合物,从而导致复制叉和DNA断裂。在未分化细胞中的HPV基因组上检测到了R环,但在分化的情况下解决了,这表明它们可能有助于调节病毒功能。在此应用中,我们将研究ATR如何调节未分化细胞中病毒dopipomes的稳定维持,以及确定分化后发生放大的细胞的稳定维护。其他工作将检查哪些DDR和复制因子与放大基因组以及这些途径如何激活相关。我们研究的总体目标是了解DNA损伤修复途径的成员如何调节依赖性HPV生命周期。

项目成果

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Laimonis A. LAIMINS其他文献

Laimonis A. LAIMINS的其他文献

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{{ truncateString('Laimonis A. LAIMINS', 18)}}的其他基金

Regulation of HPV Replication.
HPV 复制的调节。
  • 批准号:
    10347959
  • 财政年份:
    2021
  • 资助金额:
    $ 38万
  • 项目类别:
Regulation of HPV Replication.
HPV 复制的调节。
  • 批准号:
    10495235
  • 财政年份:
    2021
  • 资助金额:
    $ 38万
  • 项目类别:
Role of CTCF in HPV replication and viral DNA looping
CTCF 在 HPV 复制和病毒 DNA 循环中的作用
  • 批准号:
    9094415
  • 财政年份:
    2015
  • 资助金额:
    $ 38万
  • 项目类别:
2nd ASM Conference on Manipulation of Nuclear Processes by DNA Viruses
第二届 ASM 关于 DNA 病毒操纵核过程的会议
  • 批准号:
    8204189
  • 财政年份:
    2011
  • 资助金额:
    $ 38万
  • 项目类别:
HPV and the DNA Damage Response
HPV 和 DNA 损伤反应
  • 批准号:
    8097390
  • 财政年份:
    2010
  • 资助金额:
    $ 38万
  • 项目类别:
HPV and the DNA Damage Response
HPV 和 DNA 损伤反应
  • 批准号:
    8677767
  • 财政年份:
    2010
  • 资助金额:
    $ 38万
  • 项目类别:
Renewal: HPV and the DNA Damage Response
更新:HPV 和 DNA 损伤反应
  • 批准号:
    10612428
  • 财政年份:
    2010
  • 资助金额:
    $ 38万
  • 项目类别:
HPV and the DNA Damage Response
HPV 和 DNA 损伤反应
  • 批准号:
    7988344
  • 财政年份:
    2010
  • 资助金额:
    $ 38万
  • 项目类别:
HPV and the DNA Damage Response
HPV 和 DNA 损伤反应
  • 批准号:
    8270643
  • 财政年份:
    2010
  • 资助金额:
    $ 38万
  • 项目类别:
HPV and the DNA Damage Response
HPV 和 DNA 损伤反应
  • 批准号:
    8518050
  • 财政年份:
    2010
  • 资助金额:
    $ 38万
  • 项目类别:

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DNA 损伤感知和 ATR、范可尼贫血和 ATM 检查点激活的结构机制
  • 批准号:
    10639156
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  • 项目类别:
Renewal: HPV and the DNA Damage Response
更新:HPV 和 DNA 损伤反应
  • 批准号:
    10612428
  • 财政年份:
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  • 资助金额:
    $ 38万
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复制检查点激活和静默
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