title: The herpes simplex virus 1 UL36USP deubiquitinase suppresses DNA repair in host cells via deubiquitination of proliferating cell nuclear antigen.
abstract: 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.
authors.affiliation: State Key Lab of Protein and Plant Gene Research; Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Dong
authors.affiliation: State Key Lab of Protein and Plant Gene Research; Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Junhong
authors.initials: J
authors.lastname: Guan
authors.affiliation: Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215123, China; Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta T2N 1N4, Canada.
authors.forename: Chunfu
authors.initials: C
authors.lastname: Zheng
authors.affiliation: State Key Lab of Protein and Plant Gene Research; Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing 100871, China. Electronic address: xiaofengz@pku.edu.cn.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Zheng
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002522:Chlorocebus aethiops; D004249:DNA Damage; D004260:DNA Repair; D000072017:Deubiquitinating Enzymes / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D020125:Mutation, Missense; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism*; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000502:physiology*
chemical_list: D018809:Proliferating Cell Nuclear Antigen; C078035:UL36 protein, Human herpesvirus 1; D014764:Viral Proteins; D000072017:Deubiquitinating Enzymes
keywords: DNA damage response; DNA polymerase; UL36USP; deubiquitylation (deubiquitination); herpesvirus; proliferating cell nuclear antigen (PCNA); translesion synthesis