The NS1 protein of the parvovirus MVM Aids in the localization of the viral genome to cellular sites of DNA damage.
The NS1 protein of the parvovirus MVM Aids in the localization of the viral genome to cellular sites of DNA damage.
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DOI：
10.1371/journal.ppat.1009002
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发表时间：
2020-10
期刊：
影响因子：
6.7
通讯作者：
Pintel DJ
中科院分区：
文献类型：
--
作者：
Majumder K;Boftsi M;Whittle FB;Wang J;Fuller MS;Joshi T;Pintel DJ
自主细小病毒小鼠细小病毒（MVM）定位于细胞DNA损伤位点，以建立和维持病毒复制中心，这可以通过必需的MVM非结构磷蛋白NS1的局部沉积来可视化。这些病灶是如何建立的仍然未知。在这里，我们表明NS 1定位于DNA损伤的细胞位点，与其与病毒基因组5'末端或其共有DNA结合序列共价结合的能力无关。这些位点中的许多与病毒在感染期间占据的位点相同。然而，本地化的MVM基因组的DNA损伤位点发生时，只有野生型NS1，而不是其DNA结合突变体的表达。此外，野生型NS1，但不是它的DNA结合突变体，可以本地化的异源DNA分子含有NS1结合序列的DNA损伤位点。这些发现表明，NS1可能作为一个桥接分子，帮助MVM基因组定位到细胞DNA损伤位点，以促进正在进行的病毒复制。细小病毒是最简单的病毒之一，几乎完全依赖于宿主细胞因子来成功复制。我们以前已经表明，小鼠细小病毒（MVM）在与DNA损伤的细胞区域相关的位点建立复制中心。这些位点被引发以包含有效启动剧烈病毒裂解感染所必需的因子。病毒蛋白和病毒DNA特异性定位于这些位点的过程以前仍然未知。在这项研究中，我们表明，病毒的基本蛋白NS1具有内在的能力，本地化的DNA损伤的细胞网站。此外，野生型NS1，而不是其DNA结合突变体，可以定位到DNA损伤位点的MVM基因组，或异源DNA分子工程改造含有NS1结合位点。这项工作提供了第一个证据，表明NS 1可能作为桥梁分子发挥作用，将MVM基因组定位于DNA损伤的细胞位点，以促进持续复制。
The autonomous parvovirus Minute Virus of Mice (MVM) localizes to cellular DNA damage sites to establish and sustain viral replication centers, which can be visualized by focal deposition of the essential MVM non-structural phosphoprotein NS1. How such foci are established remains unknown. Here, we show that NS1 localized to cellular sites of DNA damage independently of its ability to covalently bind the 5’ end of the viral genome, or its consensus DNA binding sequence. Many of these sites were identical to those occupied by virus during infection. However, localization of the MVM genome to DNA damage sites occurred only when wild-type NS1, but not its DNA-binding mutant was expressed. Additionally, wild-type NS1, but not its DNA binding mutant, could localize a heterologous DNA molecule containing the NS1 binding sequence to DNA damage sites. These findings suggest that NS1 may function as a bridging molecule, helping the MVM genome localize to cellular DNA damage sites to facilitate ongoing virus replication. Parvoviruses are among the simplest of viruses, depending almost exclusively on host cell factors to successfully replicate. We have previously shown that the parvovirus Minute Virus of Mice (MVM) establishes replication centers at sites that are associated with cellular regions of DNA damage. These sites are primed to contain factors necessary to efficiently initiate vigorous virus lytic infection. The process by which viral proteins and viral DNA specifically localize to these sites has previously remained unknown. In this study we show that the essential viral protein NS1 possesses the intrinsic ability to localize to cellular sites of DNA damage. Additionally, wild-type NS1, but not its DNA binding mutant, could localize to sites of DNA damage both the MVM genome, or a heterologous DNA molecule engineered to contain NS1 binding sites. This work provides the first evidence that NS1 may function as a bridging molecule to localize the MVM genome to cellular sites of DNA damage to facilitate ongoing replication.
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