Inhibition of the herpes simplex virus type 1 DNA polymerase induces hyperphosphorylation of replication protein A and its accumulation at S-phase-specific sites of DNA damage during infection.
Inhibition of the herpes simplex virus type 1 DNA polymerase induces hyperphosphorylation of replication protein A and its accumulation at S-phase-specific sites of DNA damage during infection.
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抑制单纯疱疹病毒 1 型 DNA 聚合酶会诱导复制蛋白 A 过度磷酸化，并在感染过程中在 DNA 损伤的 S 期特异性位点积累。
DOI：
10.1128/jvi.79.11.7162-7171.2005
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Weller,SandraK
中科院分区：
文献类型：
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作者：
Wilkinson,DiannaE;Weller,SandraK
用遗传毒性物质处理哺乳动物细胞可引发DNA损伤反应，其中包括复制蛋白A(RPA)的过度磷酸化，RPA是一种在识别、信号传递和修复受损DNA方面发挥关键作用的蛋白质。我们先前已经报道，在病毒聚合酶抑制剂存在的情况下，单纯疱疹病毒1型(HSV-1)感染诱导RPA过度磷酸化(D.E.Wilkinson和S.K.Weller，J.Viro.78：4783-4796,2004)。我们发起了这项研究，以进一步表征这种对HSV-1感染的遗传毒性反应。在此，我们报道了在存在聚合酶抑制剂的情况下，感染触发了对DNA损伤的S相特异性反应，这表现为诱导RPA的过度磷酸化并在细胞周期的S相特异性的病毒灶中积聚。这种DNA损伤反应发生在病毒聚合酶抑制剂存在的情况下，需要HSV-1聚合酶全酶和病毒单链DNA结合蛋白。病毒解旋酶-Primase抑制剂的处理不会诱导RPA的过度磷酸化或其在感染细胞中的积累。综上所述，这些结果表明，S对感染的时相特异性DNA损伤反应依赖于聚合酶的特异性抑制。最后，在生产性感染期间没有诱导RPA过度磷酸化，这表明活跃的病毒复制不会触发这种潜在的有害应激反应。
The treatment of mammalian cells with genotoxic substances can trigger DNA damage responses that include the hyperphosphorylation of replication protein A (RPA), a protein that plays key roles in the recognition, signaling, and repair of damaged DNA. We have previously reported that in the presence of a viral polymerase inhibitor, herpes simplex virus type 1 (HSV-1) infection induces the hyperphosphorylation of RPA (D. E. Wilkinson and S. K. Weller, J. Virol.78:4783-4796, 2004). We initiated the present study to further characterize this genotoxic response to HSV-1 infection. Here we report that infection in the presence of polymerase inhibitors triggers an S-phase-specific response to DNA damage, as demonstrated by induction of the hyperphosphorylation of RPA and its accumulation within viral foci specific to the S phase of the cell cycle. This DNA damage response occurred in the presence of viral polymerase inhibitors and required the HSV-1 polymerase holoenzyme as well as the viral single-stranded-DNA binding protein. Treatment with an inhibitor of the viral helicase-primase did not induce the hyperphosphorylation of RPA or its accumulation in infected cells. Taken together, these results suggest that the S-phase-specific DNA damage response to infection is dependent on the specific inhibition of the polymerase. Finally, RPA hyperphosphorylation was not induced during productive infection, indicating that active viral replication does not trigger this potentially detrimental stress response.