The herpes simplex virus 1 UL36USP deubiquitinase suppresses DNA repair in host cells via deubiquitination of proliferating cell nuclear antigen
The herpes simplex virus 1 UL36USP deubiquitinase suppresses DNA repair in host cells via deubiquitination of proliferating cell nuclear antigen
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单纯疱疹病毒 1 UL36USP 去泛素酶通过增殖细胞核抗原的去泛素化抑制宿主细胞中的 DNA 修复
DOI：
10.1074/jbc.m117.778076
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发表时间：
2017-05-19
影响因子：
4.8
通讯作者：
Zheng, Xiaofeng
中科院分区：
文献类型：
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作者：
Dong, Xiaodong;Guan, Junhong;Zheng, Xiaofeng
单纯疱疹病毒1 （HSV-1）感染操纵不同的宿主dna损伤反应以促进病毒增殖，但分子机制仍有待阐明。一个可能的HSV-1靶标可能是DNA损伤耐受机制，如翻译合成（TLS）途径。在TLS中，增殖细胞核抗原（PCNA）是单泛素化的，以响应DNA损伤引起的复制叉停滞。然后，泛素化的PCNA促进了容易出错的DNA聚合酶η (polη)介导的TLS，允许分叉绕过受损位点。由于PCNA泛素化参与dna损伤修复，我们假设PCNA的功能可能被HSV-1改变。在这里，我们发现PCNA是HSV-1去泛素酶UL36USP的底物，该酶先前已被证明主要参与病毒的摄取和成熟。在hsv -1感染的细胞中，病毒感染相关的UL36USP持续降低PCNA泛素化。PCNA的去泛素化抑制了polη灶的形成，也增加了细胞对dna损伤剂的敏感性。此外，催化失活突变体UL36C40A未能使PCNA去泛素化。值得注意的是，在感染野生型HSV-1的细胞中，病毒标记基因的水平显著增加，而在UL36C40A突变型病毒感染的细胞中，病毒标记基因的水平仅适度增加，这表明UL36USP去泛素化活性支持HSV-1病毒在感染过程中的复制。这些发现表明UL36USP在DNA损伤反应途径中的作用。
Herpes simplex virus 1 (HSV-1) infection manipulates distinct host DNA-damage responses to facilitate virus proliferation, but the molecular mechanisms remain to be elucidated. One possible HSV-1 target might be DNA damage-tolerance mechanisms, such as the translesion synthesis (TLS) pathway. In TLS, proliferating cell nuclear antigen (PCNA) is monoubiquitinated in response to DNA damage-caused replication fork stalling. Ubiquitinated PCNA then facilitates the error-prone DNA polymerase η (polη)-mediated TLS, allowing the fork to bypass damaged sites. Because of the involvement of PCNA ubiquitination in DNA-damage repair, we hypothesized that the function of PCNA might be altered by HSV-1. Here we show that PCNA is a substrate of the HSV-1 deubiquitinase UL36USP, which has previously been shown to be involved mainly in virus uptake and maturation. In HSV-1-infected cells, viral infection-associated UL36USP consistently reduced PCNA ubiquitination. The deubiquitination of PCNA inhibited the formation of polη foci and also increased cell sensitivity to DNA-damage agents. Moreover, the catalytically inactive mutant UL36C40A failed to deubiquitinate PCNA. Of note, the levels of virus marker genes increased strikingly in cells infected with wild-type HSV-1, but only moderately in UL36C40A mutant virus-infected cells, indicating that the UL36USP deubiquitinating activity supports HSV-1 virus replication during infection. These findings suggest a role of UL36USP in the DNA damage-response pathway.