Viral Modulation of Genetic Stability

遗传稳定性的病毒调节

基本信息

项目摘要

DESCRIPTION (provided by applicant): Viruses elicit multifaceted responses from the cells that they infect. Among the antiviral defenses of the host cell is activation of a DNA damage response. In the case of adenovirus (Ad) infection, the double-stranded, linear DNA genomes represent substrates for cellular DNA repair pathways that result in Ad genomes being joined into concatemers during infection with viruses deleted of the E4 open reading frames. Concatemerization requires host DNA repair proteins, including the Mre11/Rad50/Nbs1 complex (MRN). Infection with E4-deleted Ad is accompanied by activation of the cellular DNA damage signaling cascades. The DNA damage response is inactivated during wild-type Ad infection by the products of the early region E4. The E4orf3 protein forms intranuclear track structures, which sequester the MRN proteins and prevent ATR damage signaling. The E4orf6 protein forms a complex with E1b55K that recruits cellular proteins to form an E3 ligase that targets cellular repair factors for degradation, including MRN and ligase IV proteins. This proposal probes mechanistic aspects of the cellular response to adenovirus infection and its impact on the viral lifecycle. We show that MRN inhibits virus DNA replication, identify a role for the CtIP protein, and suggest a model that involves removal of the terminal protein from the virus genome. In the first Aim we will address the impact of the cellular repair proteins on virus infection and test the model for inhibition. The subsequent two Aims will address ways in which E4 proteins counteract these host antiviral functions. In Aim 2 we will study the mechanism used by E1b55K/E4orf6 to target cellular factors for proteasomal degradation, and the impact on virus replication. Aim 3 will focus on Ad E4orf3, and will investigate the correlation between disruption of PML bodies, mis-localization of the MRN complex, prevention of concatemer formation, inhibition of damage signaling, and production of late proteins by E4orf3. These studies will elucidate the biological relevance of the interactions between cellular repair factors and viral proteins, and will have broader implications for our understanding of cellular DNA damage responses. PUBLIC HEALTH RELEVANCE: Viruses elicit multifaceted responses from the cells that they infect, among which is activation of a DNA damage response. The cellular DNA repair machinery acts to inhibit adenovirus, and this is counteracted by viral proteins that inactivate the DNA damage apparatus. Studying these interactions will provide mechanistic insights into virus infections, and cellular processes that recognize and repair damaged DNA.
描述(由申请人提供):病毒从它们感染的细胞中引发多方面的反应。宿主细胞的抗病毒防御包括激活DNA损伤反应。在腺病毒(Ad)感染的情况下,双链、线性DNA基因组代表细胞DNA修复途径的底物,该途径导致在感染E4开放阅读框缺失的病毒时,Ad基因组加入串联蛋白。连锁化需要宿主DNA修复蛋白,包括Mre11/Rad50/Nbs1复合体(MRN)。感染E4缺失的Ad伴随着细胞DNA损伤信号级联的激活。在野生型Ad感染过程中,DNA损伤反应被早期区域E4的产物灭活。E4orf3蛋白在核内形成径迹结构,隔离MRN蛋白,阻止ATR损伤信号。E4orf6蛋白与E1b55K形成复合体,招募细胞蛋白形成E3连接酶,针对细胞修复因子进行降解,包括MRN和连接酶IV蛋白。这项建议探索腺病毒感染的细胞反应的机制方面及其对病毒生命周期的影响。我们证明了MRN抑制病毒DNA复制,确定了CtIP蛋白的作用,并提出了一个涉及从病毒基因组中移除末端蛋白的模型。在第一个目标中,我们将解决细胞修复蛋白对病毒感染的影响,并测试该模型的抑制作用。接下来的两个目标将解决E4蛋白中和这些宿主抗病毒功能的方式。在目标2中,我们将研究E1b55K/E4orf6靶向蛋白酶体降解的细胞因子的机制,以及对病毒复制的影响。目的3将重点放在AdE4orf3上,并将研究PML小体的破坏、MRN复合体的错位、防止串联形成、损伤信号的抑制以及E4orf3产生晚期蛋白之间的关系。这些研究将阐明细胞修复因子和病毒蛋白之间相互作用的生物学相关性,并将对我们理解细胞DNA损伤反应具有更广泛的意义。与公共卫生相关:病毒从它们感染的细胞中引发多方面的反应,其中之一是激活DNA损伤反应。细胞DNA修复机制起到抑制腺病毒的作用,这种作用被使DNA损伤机制失活的病毒蛋白所抵消。研究这些相互作用将提供对病毒感染以及识别和修复受损DNA的细胞过程的机械性见解。

项目成果

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Matthew D. Weitzman其他文献

Recruitment of wild-type and recombinant adeno-associated virus into adenovirus replication centers
将野生型和重组腺相关病毒招募到腺病毒复制中心
  • DOI:
  • 发表时间:
    1996
  • 期刊:
  • 影响因子:
    5.4
  • 作者:
    Matthew D. Weitzman;K. Fisher;James M. Wilson
  • 通讯作者:
    James M. Wilson
Probing condensate microenvironments with a micropeptide killswitch
用微肽杀手探针探测冷凝液微环境
  • DOI:
    10.1038/s41586-025-09141-5
  • 发表时间:
    2025-06-04
  • 期刊:
  • 影响因子:
    48.500
  • 作者:
    Yaotian Zhang;Ida Stöppelkamp;Pablo Fernandez-Pernas;Melanie Allram;Matthew Charman;Alexandre P. Magalhaes;Melanie Piedavent-Salomon;Gregor Sommer;Yu-Chieh Sung;Katrina Meyer;Nicholas Grams;Edwin Halko;Shivali Dongre;David Meierhofer;Michal Malszycki;Ibrahim A. Ilik;Tugce Aktas;Matthew L. Kraushar;Nadine Vastenhouw;Matthew D. Weitzman;Florian Grebien;Henri Niskanen;Denes Hnisz
  • 通讯作者:
    Denes Hnisz
Interaction of wild-type and mutant adeno-associated virus (AAV) Rep proteins on AAV hairpin DNA
野生型和突变型腺相关病毒 (AAV) Rep 蛋白在 AAV 发夹 DNA 上的相互作用
  • DOI:
  • 发表时间:
    1996
  • 期刊:
  • 影响因子:
    5.4
  • 作者:
    Matthew D. Weitzman;S. R. Kyöstiö;Barrie J. Carter;R. Owens
  • 通讯作者:
    R. Owens
A Tribute to Barrie Carter.
向巴里·卡特致敬。
  • DOI:
  • 发表时间:
    2020
  • 期刊:
  • 影响因子:
    4.2
  • 作者:
    A. Srivastava;Matthew D. Weitzman;S. Chatterjee;J. Engelhardt;R. Owens;Nick Muzyczka;Robin Ali
  • 通讯作者:
    Robin Ali
Live Cell Fluorescence Correlation Spectroscopy with Real Time Photoactivation Feedback
  • DOI:
    10.1016/j.bpj.2012.11.3181
  • 发表时间:
    2013-01-29
  • 期刊:
  • 影响因子:
  • 作者:
    Matthew D. Weitzman;Chandran R. Sabanayagam;Kenneth L. van Golen
  • 通讯作者:
    Kenneth L. van Golen

Matthew D. Weitzman的其他文献

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{{ truncateString('Matthew D. Weitzman', 18)}}的其他基金

Non-canonical chimeric proteins generated during Adenovirus infection
腺病毒感染期间产生的非典型嵌合蛋白
  • 批准号:
    10448505
  • 财政年份:
    2021
  • 资助金额:
    $ 36.02万
  • 项目类别:
Ubiquitination during infection with Mouse Adenovirus
小鼠腺病毒感染过程中的泛素化
  • 批准号:
    10152932
  • 财政年份:
    2021
  • 资助金额:
    $ 36.02万
  • 项目类别:
Non-canonical chimeric proteins generated during Adenovirus infection
腺病毒感染期间产生的非典型嵌合蛋白
  • 批准号:
    10312411
  • 财政年份:
    2021
  • 资助金额:
    $ 36.02万
  • 项目类别:
Ubiquitination during infection with Mouse Adenovirus
小鼠腺病毒感染过程中的泛素化
  • 批准号:
    10364682
  • 财政年份:
    2021
  • 资助金额:
    $ 36.02万
  • 项目类别:
Double-stranded RNA during DNA virus infection
DNA病毒感染期间的双链RNA
  • 批准号:
    9886201
  • 财政年份:
    2019
  • 资助金额:
    $ 36.02万
  • 项目类别:
Double-stranded RNA during DNA virus infection
DNA病毒感染期间的双链RNA
  • 批准号:
    10092100
  • 财政年份:
    2019
  • 资助金额:
    $ 36.02万
  • 项目类别:
Double-stranded RNA during DNA virus infection
DNA病毒感染期间的双链RNA
  • 批准号:
    10359055
  • 财政年份:
    2019
  • 资助金额:
    $ 36.02万
  • 项目类别:
Double-stranded RNA during DNA virus infection
DNA病毒感染期间的双链RNA
  • 批准号:
    9764127
  • 财政年份:
    2019
  • 资助金额:
    $ 36.02万
  • 项目类别:
Double-stranded RNA during DNA virus infection
DNA病毒感染期间的双链RNA
  • 批准号:
    10571919
  • 财政年份:
    2019
  • 资助金额:
    $ 36.02万
  • 项目类别:
Adenovirus manipulation of cellular chromatin to overcome host responses
腺病毒操纵细胞染色质以克服宿主反应
  • 批准号:
    10238103
  • 财政年份:
    2018
  • 资助金额:
    $ 36.02万
  • 项目类别:

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    7590935
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    2009
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Mechanisms of ATM activation
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  • 批准号:
    8030422
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    2009
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Mechanisms of ATM activation
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ATM 激活及其在 DNA 损伤反应中的功能重要性
  • 批准号:
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    2009
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    $ 36.02万
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Mechanisms of ATM activation
ATM 激活机制
  • 批准号:
    8444602
  • 财政年份:
    2009
  • 资助金额:
    $ 36.02万
  • 项目类别:
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