title: Activation of ATR-Chk1 pathway facilitates EBV-mediated transformation of primary tonsillar B-cells.
abstract: Primary infection of the immunocompromised host with the oncovirus Epstein-Barr virus (EBV) that targets mainly B-cells is associated with an increased risk for EBV-associated tumors. The early events subsequent to primary infection with potential for B-cell transformation are poorly studied. Here, we modeled in vitro the primary infection by using B-cells isolated from tonsils, the portal of entry of EBV, since species specificity of EBV hampers modeling in experimental animals. Increasing evidence indicates that the host DNA damage response (DDR) can influence and be influenced by EBV infection. Thus, we inoculated tonsillar B-cells (TBCs) with EBV-B95.8 and investigated cell proliferation and the DDR during the first 96 hours thereafter. We identified for the first time that EBV infection of TBCs induces a period of hyperproliferation 48-96 hours post infection characterized by the activation of ataxia telangiectasia and Rad3-releated (ATR) and checkpoint kinase-1 (Chk1). Whereas inhibition of Chk1 did not affect B-cell transformation, the specific inhibition of ATR robustly decreased the transformation efficiency of EBV. Our results suggest that activation of ATR is key for EBV-induced B-cell transformation. Thus, targeting the interaction between ATR/Chk1 and EBV could offer new options for the treatment of EBV-associated malignancies.
authors.affiliation: Experimental Infectious Diseases and Cancer Research, University Children's Hospital of Zürich, Zürich, Switzerland.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Mordasini
authors.affiliation: Experimental Infectious Diseases and Cancer Research, University Children's Hospital of Zürich, Zürich, Switzerland.|Department of Otolaryngology-Head & Neck Surgery, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Seigo
authors.initials: S
authors.lastname: Ueda
authors.affiliation: Experimental Infectious Diseases and Cancer Research, University Children's Hospital of Zürich, Zürich, Switzerland.
authors.forename: Roberta
authors.initials: R
authors.lastname: Aslandogmus
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Children's Hospital of Zürich, Zürich, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Berger
authors.affiliation: Division of Otolaryngology, University Children's Hospital of Zürich, Zürich, Switzerland.
authors.forename: Claudine
authors.initials: C
authors.lastname: Gysin
authors.affiliation: Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Hühn
authors.affiliation: Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland.
authors.forename: Alessandro A
authors.initials: AA
authors.lastname: Sartori
authors.affiliation: Experimental Infectious Diseases and Cancer Research, University Children's Hospital of Zürich, Zürich, Switzerland.
authors.forename: Michele
authors.initials: M
authors.lastname: Bernasconi
authors.affiliation: Experimental Infectious Diseases and Cancer Research, University Children's Hospital of Zürich, Zürich, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Nadal
mesh_terms: D018941:Antigens, CD19 / Q000378:metabolism; D064007:Ataxia Telangiectasia Mutated Proteins / Q000032:analysis / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000821:virology*; D023201:CD40 Ligand / Q000378:metabolism; D049109:Cell Proliferation; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D000071877:Checkpoint Kinase 1 / Q000032:analysis / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D004789:Enzyme Activation; D020031:Epstein-Barr Virus Infections / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000821:virology*; D004854:Herpesvirus 4, Human / Q000276:immunology / Q000472:pathogenicity*; D054884:Host-Pathogen Interactions; D006801:Humans; D014066:Palatine Tonsil / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology / Q000821:virology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D018941:Antigens, CD19; C000604811:CD19 molecule, human; D047428:Protein Kinase Inhibitors; D023201:CD40 Ligand; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1
keywords: ATR; Chk1; DDR; EBV; hyperproliferation