Parvovirus minute virus of mice induces a DNA damage response that facilitates viral replication.
Parvovirus minute virus of mice induces a DNA damage response that facilitates viral replication.
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DOI：
10.1371/journal.ppat.1001141
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发表时间：
2010-10-07
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：
Adeyemi RO;Landry S;Davis ME;Weitzman MD;Pintel DJ
DNA病毒感染可引起宿主细胞的DNA损伤反应（DDRs）。在某些情况下，DDR对病毒复制提供了必须克服的阻断，并且在其他情况下，感染因子利用DDR来促进复制。我们发现，与自主细小病毒微小病毒的小鼠（MVM）的低多重感染的结果在DDR的激活，其特征在于磷酸化的H2AX，Nbs1，RPA 32，Chk2和p53。这些蛋白质被募集到MVM复制中心，在那里它们与主要的病毒复制蛋白NS1共定位。在用MVMp或MVMi菌株感染后，在人和鼠细胞系中均观察到该应答。病毒的复制是DNA损伤信号传导所必需的。损伤反应蛋白，包括ATM激酶，积累在病毒诱导的复制中心。使用突变细胞系和特异性激酶抑制剂，我们表明ATM是正常小鼠宿主中信号事件的主要转换器。ATM抑制剂限制MVM复制并改善病毒诱导的细胞周期停滞，表明DNA损伤信号促进病毒复制，可能部分通过促进细胞周期停滞。因此，似乎MVM利用感染早期的细胞DNA损伤反应机制来增强其在宿主细胞中的复制。DNA病毒感染可导致细胞DNA损伤反应的诱导。这些强有力的反应可以阻止某些病毒的复制，但也可以被其他病毒利用。我们在这里表明，自主细小病毒，单链线性DNA病毒，感染许多动物物种，包括人类，可以诱导一个强大的DNA损伤反应后，低多重感染。该反应依赖于活跃的病毒复制，并且共济失调毛细血管扩张突变（ATM）激酶是正常鼠宿主中信号传导事件的主要换能器。ATM抑制剂限制MVM复制并克服病毒诱导的细胞周期停滞。因此，响应细小病毒复制的DNA损伤信号促进病毒复制，可能部分通过促进细胞周期停滞。我们的研究结果表明，MVM利用方面的细胞DNA损伤反应机制在感染早期，以提高其在宿主细胞中的复制。
Infection by DNA viruses can elicit DNA damage responses (DDRs) in host cells. In some cases the DDR presents a block to viral replication that must be overcome, and in other cases the infecting agent exploits the DDR to facilitate replication. We find that low multiplicity infection with the autonomous parvovirus minute virus of mice (MVM) results in the activation of a DDR, characterized by the phosphorylation of H2AX, Nbs1, RPA32, Chk2 and p53. These proteins are recruited to MVM replication centers, where they co-localize with the main viral replication protein, NS1. The response is seen in both human and murine cell lines following infection with either the MVMp or MVMi strains. Replication of the virus is required for DNA damage signaling. Damage response proteins, including the ATM kinase, accumulate in viral-induced replication centers. Using mutant cell lines and specific kinase inhibitors, we show that ATM is the main transducer of the signaling events in the normal murine host. ATM inhibitors restrict MVM replication and ameliorate virus-induced cell cycle arrest, suggesting that DNA damage signaling facilitates virus replication, perhaps in part by promoting cell cycle arrest. Thus it appears that MVM exploits the cellular DNA damage response machinery early in infection to enhance its replication in host cells. Infection by DNA viruses can result in the induction of cellular DNA damage responses. These potent responses can present a block to the replication of certain viruses, but can also be utilized by others to their advantage. We show here that autonomous parvoviruses, single-stranded linear DNA viruses that infect many animal species including humans, can induce a strong DNA damage response following low multiplicity of infection. The response is dependent upon active viral replication, and the ataxia telangiectasia mutated (ATM) kinase is the main transducer of the signaling events in the normal murine host. Inhibitors of ATM restrict MVM replication and overcome virus-induced cell cycle arrest. Thus, DNA damage signaling in response to parvovirus replication facilitates virus replication, perhaps in part by promoting cell cycle arrest. Our results suggest that MVM exploits aspects of the cellular DNA damage response machinery early in infection to enhance its replication in host cells.
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