Adenovirus Core Protein VII Downregulates the DNA Damage Response on the Host Genome
Adenovirus Core Protein VII Downregulates the DNA Damage Response on the Host Genome
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DOI：
10.1128/jvi.01089-17
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发表时间：
2017-10-01
影响因子：
5.4
通讯作者：
Weitzman, Matthew D.
中科院分区：
文献类型：
--
作者：
Avgousti, Daphne C.;Della Fera, Ashley N.;Weitzman, Matthew D.
病毒操纵细胞蛋白质使病毒能够抑制宿主防御并产生感染性后代。由于腺病毒基因组的线性双链DNA性质，细胞DNA损伤反应（DDR）被认为是成功感染的障碍。腺病毒基因组与蛋白VII包装在一起，蛋白VII是一种病毒编码的组蛋白样核心蛋白，被认为可以保护进入的病毒基因组免受细胞DNA损伤机制的检测。我们发现，蛋白VII在感染过程中定位于宿主染色质，这使我们假设蛋白VII可能影响细胞基因组上的DNA损伤反应。在这里，我们表明，蛋白VII在细胞染色质的结果在一个显着减少的积累磷酸化H2 AX（γ H2 AX）照射后，表明蛋白VII抑制DDR信号。癌蛋白SET最近被认为通过影响修复蛋白进入染色质来调节DDR。由于蛋白质VII结合SET，我们研究了SET在蛋白质VII的DDR抑制中的作用。我们发现，敲低SET部分挽救了蛋白VII诱导的宿主基因组上γ H2 AX积累的减少，这表明SET是抑制所需的。最后，我们表明，敲除SET也允许ATM本地化到传入的病毒基因组结合蛋白VII感染过程中缺乏早期E4区的突变体。总之，我们的数据表明，蛋白VII-SET相互作用有助于腺病毒的DDR逃避。我们的研究结果提供了一个额外的例子，腺病毒所使用的策略，废除宿主DDR，并显示病毒如何可以通过操纵宿主chromatin.IMPORTANCE修改细胞过程的DNA损伤反应（DDR）是一个细胞网络，这是至关重要的是维持基因组的完整性。在细胞核中复制的DNA病毒挑战常驻基因组，并且必须克服细胞反应，包括DDR。腺病毒是人类常见的病原体，可引起多种疾病，如呼吸道感染和结膜炎。在这里，我们描述了一个小的腺病毒核心蛋白，在感染过程中定位到宿主染色质可以全局下调DDR。我们的研究集中在损伤信号通路中的关键参与者，并强调了病毒对染色质的操纵如何影响DDR蛋白进入宿主基因组。
Viral manipulation of cellular proteins allows viruses to suppress host defenses and generate infectious progeny. Due to the linear double-stranded DNA nature of the adenovirus genome, the cellular DNA damage response (DDR) is considered a barrier to successful infection. The adenovirus genome is packaged with protein VII, a virally encoded histone-like core protein that is suggested to protect incoming viral genomes from detection by the cellular DNA damage machinery. We showed that protein VII localizes to host chromatin during infection, leading us to hypothesize that protein VII may affect DNA damage responses on the cellular genome. Here we show that protein VII at cellular chromatin results in a significant decrease in accumulation of phosphorylated H2AX (gamma H2AX) following irradiation, indicating that protein VII inhibits DDR signaling. The oncoprotein SET was recently suggested to modulate the DDR by affecting access of repair proteins to chromatin. Since protein VII binds SET, we investigated a role for SET in DDR inhibition by protein VII. We show that knockdown of SET partially rescues the protein VII-induced decrease in gamma H2AX accumulation on the host genome, suggesting that SET is required for inhibition. Finally, we show that knockdown of SET also allows ATM to localize to incoming viral genomes bound by protein VII during infection with a mutant lacking early region E4. Together, our data suggest that the protein VII-SET interaction contributes to DDR evasion by adenovirus. Our results provide an additional example of a strategy used by adenovirus to abrogate the host DDR and show how viruses can modify cellular processes through manipulation of host chromatin.IMPORTANCE The DNA damage response (DDR) is a cellular network that is crucial for maintaining genome integrity. DNA viruses replicating in the nucleus challenge the resident genome and must overcome cellular responses, including the DDR. Adenoviruses are prevalent human pathogens that can cause a multitude of diseases, such as respiratory infections and conjunctivitis. Here we describe how a small adenovirus core protein that localizes to host chromatin during infection can globally downregulate the DDR. Our study focuses on key players in the damage signaling pathway and highlights how viral manipulation of chromatin may influence access of DDR proteins to the host genome.