title: Activation of ataxia telangiectasia-mutated DNA damage checkpoint signal transduction elicited by herpes simplex virus infection.
abstract: Eukaryotic cells are equipped with machinery to monitor and repair damaged DNA. Herpes simplex virus (HSV) DNA replication occurs at discrete sites in nuclei, the replication compartment, where viral replication proteins cluster and synthesize a large amount of viral DNA. In the present study, HSV infection was found to elicit a cellular DNA damage response, with activation of the ataxia-telangiectasia-mutated (ATM) signal transduction pathway, as observed by autophosphorylation of ATM and phosphorylation of multiple downstream targets including Nbs1, Chk2, and p53, while infection with a UV-inactivated virus or with a replication-defective virus did not. Activated ATM and the DNA damage sensor MRN complex composed of Mre11, Rad50, and Nbs1 were recruited and retained at sites of viral DNA replication, probably recognizing newly synthesized viral DNAs as abnormal DNA structures. These events were not observed in ATM-deficient cells, indicating ATM dependence. In Nbs1-deficient cells, HSV infection induced an ATM DNA damage response that was delayed, suggesting a functional MRN complex requirement for efficient ATM activation. However, ATM silencing had no effect on viral replication in 293T cells. Our data open up an interesting question of how the virus is able to complete its replication, although host cells activate ATM checkpoint signaling in response to the HSV infection.
authors.affiliation: Division of Virology, Aichi Cancer Center Research Institute, 1-1, Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Shirata
authors.forename: Ayumi
authors.initials: A
authors.lastname: Kudoh
authors.forename: Tohru
authors.initials: T
authors.lastname: Daikoku
authors.forename: Yasutoshi
authors.initials: Y
authors.lastname: Tatsumi
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Fujita
authors.forename: Tohru
authors.initials: T
authors.lastname: Kiyono
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Sugaya
authors.forename: Hiroki
authors.initials: H
authors.lastname: Isomura
authors.forename: Kanji
authors.initials: K
authors.lastname: Ishizaki
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Tsurumi
mesh_terms: D017766:Acid Anhydride Hydrolases; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002460:Cell Line; D064447:Checkpoint Kinase 2; D002522:Chlorocebus aethiops; D004249:DNA Damage; D045643:DNA Repair Enzymes / Q000378:metabolism; D004279:DNA, Viral; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D005347:Fibroblasts / Q000378:metabolism; D020868:Gene Silencing; D006566:Herpesviridae Infections / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D017404:In Situ Hybridization, Fluorescence; D007700:Kinetics; D000076228:MRE11 Homologue Protein; D008856:Microscopy, Fluorescence; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D018139:Simplexvirus / Q000378:metabolism*; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D014466:Ultraviolet Rays; D015854:Up-Regulation; D014709:Vero Cells
chemical_list: D018797:Cell Cycle Proteins; D004279:DNA, Viral; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; C112156:NBN protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; D000076228:MRE11 Homologue Protein; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes