SV40 Large T Antigen Interference with DNA Damage Checkpoints

SV40 大 T 抗原干扰 DNA 损伤检查点

基本信息

  • 批准号:
    6989680
  • 负责人:
  • 金额:
    $ 15.76万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2004
  • 资助国家:
    美国
  • 起止时间:
    2004-04-27 至 2009-02-28
  • 项目状态:
    已结题

项目摘要

The SV40 large T antigen (T Ag) has the ability to transactivate a variety of cellular and viral promoters. However, it is not known whether the ability of T Ag to activate transcription contributes to cell growth and transformation. In the previous grant period, we used the temperature sensitive cell line, ts13, to address this question. The ts13 cell line contains a point substitution mutation in TAF1, an essential component of the core transcription complex TFIID. Upon shift from the permissive temperature to the restrictive temperature, ts13 cells undergo a growth arrest in the G1 phase of the cell cycle. Furthermore, transcription from a limited number of promoters is significantly reduced in ts13 cells at the restrictive temperature. T Ag is capable of overriding the growth arrest as well as the transcriptional defects in the ts13 cell line at the restrictive temperature. Our efforts led to the unexpected findings that the growth arrest and perhaps the transcription defects in ts13 cells reflected activation of a DNA damage checkpoint and that T Ag can inactivate or bypass both of these DNA damage signals. We observed that T Ag's p53 and pRb binding domains override the growth arrest and the DNA binding domain (DBD) rescues the transcriptional defects. These two effects of T Ag on ts13 cells may reflect two independent mechanisms that T Ag has evolved to overcome DNA damage checkpoints. We propose that the TAF1 defect triggers a DNA damage response that mediates growth arrest through activation of p53. In addition, the transcription defects may also reflect a DNA damage response. To address these issues, we propose the following Specific Aims: 1. Determine if the ability of the T Ag DBD to rescue the transcriptional defect in ts13 cells is due to interference with a DNA damage checkpoint or rescue of transcriptional activation. 2. We will explore the specific contribution of TAF1 to the DNA damage signal by examining the role of its histone acetyl transferase (HAT) and ubiquitin-activating/conjugating (Ubac) activities. 3. Determine the DNA damage factors activated in ts13 at the restrictive temperature and contrast with activation of the intra-S phase and double strand break DNA damage checkpoints. We will examine the ability of T Ag to perturb recruitment of factors to sites of DNA damage. 4. Generate a mouse model of the ts13/TAF1 defect to explore the genetic interaction between transcription and DNA damage checkpoint response.
SV 40大T抗原(T Ag)具有反式激活多种细胞和病毒启动子的能力。然而,目前尚不清楚T抗原激活转录的能力是否 有助于细胞生长和转化。在上一个资助期,我们使用温度敏感细胞株ts 13来解决这个问题。ts 13细胞系含有TAF 1的点取代突变,TAF 1是核心转录复合物TFIID的重要组成部分。在从允许温度转变到限制温度时,ts 13细胞在细胞周期的G1期经历生长停滞。此外,从有限数量的启动子的转录显着减少在限制性温度下的ts 13细胞。在限制性温度下,T Ag能够克服ts 13细胞系中的生长停滞以及转录缺陷。我们的努力导致了意想不到的发现,即ts 13细胞中的生长停滞和可能的转录缺陷反映了DNA损伤检查点的激活,并且T Ag可以抑制或绕过这两种DNA损伤信号。我们观察到T Ag的p53和pRb结合结构域覆盖生长停滞,DNA结合结构域(DBD)拯救转录缺陷。T抗原对ts 13细胞的这两种作用可能反映了T抗原克服DNA损伤检查点的两种独立机制。我们认为TAF 1缺陷引发DNA损伤反应,通过激活p53介导生长停滞。此外,转录缺陷也可能反映DNA损伤反应。为了解决这些问题,我们提出以下具体目标: 1.确定T Ag DBD拯救ts 13细胞中转录缺陷的能力是否是由于干扰DNA损伤检查点或拯救转录激活。 2.我们将通过研究TAF 1的组蛋白乙酰转移酶(HAT)和泛素激活/结合(Ubac)活性来探索TAF 1对DNA损伤信号的具体贡献。 3.测定限制性温度下ts 13中激活的DNA损伤因子,并与S期内和双链断裂DNA损伤检查点的激活进行对比。我们将研究T抗原干扰DNA损伤位点因子募集的能力。 4.建立ts 13/TAF 1缺陷小鼠模型,探索转录和DNA损伤检查点反应之间的遗传相互作用。

项目成果

期刊论文数量(0)
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会议论文数量(0)
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James A. DeCaprio其他文献

The DREAM complex: master coordinator of cell cycle-dependent gene expression
DREAM 复合物:细胞周期依赖性基因表达的主要协调者
  • DOI:
    10.1038/nrc3556
  • 发表时间:
    2013-07-11
  • 期刊:
  • 影响因子:
    66.800
  • 作者:
    Subhashini Sadasivam;James A. DeCaprio
  • 通讯作者:
    James A. DeCaprio
IMPDH inhibition induces DNA replication stress and ATR sensitivity in Merkel cell carcinoma
IMPDH抑制在默克尔细胞癌中诱导DNA复制应激和ATR敏感性
  • DOI:
    10.1016/j.isci.2025.112567
  • 发表时间:
    2025-06-20
  • 期刊:
  • 影响因子:
    4.100
  • 作者:
    Julia L. Schnabel;Thomas C. Frost;Adam C. Wang;Varsha Ananthapadmanabhan;Satvik Gurram;Kara M. Soroko;Prafulla C. Gokhale;James A. DeCaprio
  • 通讯作者:
    James A. DeCaprio
Epidemiology, biology and therapy of Merkel cell carcinoma: conclusions from the EU project IMMOMEC
  • DOI:
    10.1007/s00262-017-2099-3
  • 发表时间:
    2017-11-30
  • 期刊:
  • 影响因子:
    5.100
  • 作者:
    Jürgen C. Becker;Andreas Stang;Axel zur Hausen;Nicole Fischer;James A. DeCaprio;Richard W. Tothill;Rikke Lyngaa;Ulla Kring Hansen;Cathrin Ritter;Paul Nghiem;Christopher K. Bichakjian;Selma Ugurel;David Schrama
  • 通讯作者:
    David Schrama
Milademetan is a highly potent MDM2 inhibitor in TP53 wild-type (p53 WT) models of Merkel cell carcinoma (MCC)
  • DOI:
    10.1016/j.jid.2022.08.004
  • 发表时间:
    2022-10-01
  • 期刊:
  • 影响因子:
  • 作者:
    Varsha Ananthapadmanabhan;Thomas C. Frost;Kara M. Soroko;Aine Knott;Brianna Magliozzi;Prafulla C. Gokhale;Vijaya Tirunagaru;Robert C. Doebele;James A. DeCaprio
  • 通讯作者:
    James A. DeCaprio
Association between treatment center experience and survival after diagnosis of stage I to III Merkel cell carcinoma treated with surgery with or without postoperative radiation therapy
  • DOI:
    10.1016/j.jaad.2020.10.089
  • 发表时间:
    2021-03-01
  • 期刊:
  • 影响因子:
  • 作者:
    Fallon E. Chipidza;Manisha Thakuria;Jonathan D. Schoenfeld;Ann W. Silk;Paul J. Catalano;Charles H. Yoon;Glenn J. Hanna;James A. DeCaprio;Roy B. Tishler;Danielle N. Margalit
  • 通讯作者:
    Danielle N. Margalit

James A. DeCaprio的其他文献

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{{ truncateString('James A. DeCaprio', 18)}}的其他基金

Identification of Novel Oncogenic Signaling Pathways using Viral Perturbations
利用病毒扰动鉴定新型致癌信号通路
  • 批准号:
    10460971
  • 财政年份:
    2019
  • 资助金额:
    $ 15.76万
  • 项目类别:
Identification of Novel Oncogenic Signaling Pathways using Viral Perturbations
利用病毒扰动鉴定新型致癌信号通路
  • 批准号:
    10411425
  • 财政年份:
    2019
  • 资助金额:
    $ 15.76万
  • 项目类别:
Identification of Novel Oncogenic Signaling Pathways using Viral Perturbations
利用病毒扰动鉴定新型致癌信号通路
  • 批准号:
    10664906
  • 财政年份:
    2019
  • 资助金额:
    $ 15.76万
  • 项目类别:
Identification of Novel Oncogenic Signaling Pathways using Viral Perturbations
利用病毒扰动鉴定新型致癌信号通路
  • 批准号:
    9816351
  • 财政年份:
    2019
  • 资助金额:
    $ 15.76万
  • 项目类别:
Identification of Novel Oncogenic Signaling Pathways using Viral Perturbations
利用病毒扰动鉴定新型致癌信号通路
  • 批准号:
    10222618
  • 财政年份:
    2019
  • 资助金额:
    $ 15.76万
  • 项目类别:
CORE 2: Administrative Core
核心 2:行政核心
  • 批准号:
    10227788
  • 财政年份:
    2017
  • 资助金额:
    $ 15.76万
  • 项目类别:
Program Integration
程序整合
  • 批准号:
    9981668
  • 财政年份:
    2017
  • 资助金额:
    $ 15.76万
  • 项目类别:
Young Empowered Scientists for ContinUed Research Engagement (YES for CURE)
赋权年轻科学家继续参与研究(CURE 是)
  • 批准号:
    9416355
  • 财政年份:
    2017
  • 资助金额:
    $ 15.76万
  • 项目类别:
PROJECT 1: Merkel Cell Carcinoma, Merkel Cell Polyomavirus and PP2A (James A. DeCaprio)
项目 1:默克尔细胞癌、默克尔细胞多瘤病毒和 PP2A (James A. DeCaprio)
  • 批准号:
    9981670
  • 财政年份:
    2017
  • 资助金额:
    $ 15.76万
  • 项目类别:
CORE 2: Administrative Core
核心 2:行政核心
  • 批准号:
    9981677
  • 财政年份:
    2017
  • 资助金额:
    $ 15.76万
  • 项目类别:

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