Activation of ATR-Chk1 pathway facilitates EBV-mediated transformation of primary tonsillar B-cells
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Vanessa Mordasini1, Seigo Ueda1,2, Roberta Aslandogmus1, Christoph Berger3, Claudine Gysin4, Daniela Hühn5, Alessandro A. Sartori5, Michele Bernasconi1,*, David Nadal1,*
1Experimental Infectious Diseases and Cancer Research, University Children’s Hospital of Zürich, Zürich, Switzerland
2Department of Otolaryngology-Head & Neck Surgery, Asahikawa Medical University, Asahikawa, Japan
3Division of Infectious Diseases and Hospital Epidemiology, University Children’s Hospital of Zürich, Zürich, Switzerland
4Division of Otolaryngology, University Children’s Hospital of Zürich, Zürich, Switzerland
5Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland
*These authors contributed equally to this work
David Nadal, email: firstname.lastname@example.org
Keywords: EBV, DDR, ATR, Chk1, hyperproliferation
Received: October 04, 2016 Accepted: December 18, 2016 Published: December 23, 2016
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.
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