title: An ATM/Chk2-mediated DNA damage-responsive signaling pathway suppresses Epstein-Barr virus transformation of primary human B cells.
abstract: Epstein-Barr virus (EBV), an oncogenic herpesvirus that causes human malignancies, infects and immortalizes primary human B cells in vitro into indefinitely proliferating lymphoblastoid cell lines, which represent a model for EBV-induced tumorigenesis. The immortalization efficiency is very low, suggesting that an innate tumor suppressor mechanism is operative. We identify the DNA damage response (DDR) as a major component of the underlying tumor suppressor mechanism. EBV-induced DDR activation was not due to lytic viral replication, nor did the DDR marks colocalize with latent episomes. Rather, a transient period of EBV-induced hyperproliferation correlated with DDR activation. Inhibition of the DDR kinases ATM and Chk2 markedly increased transformation efficiency of primary B cells. Further, the viral latent oncoprotein EBNA3C was required to attenuate the EBV-induced DDR. We propose that heightened oncogenic activity in early cell divisions activates a growth-suppressive DDR that is attenuated by viral latency products to induce cell immortalization.
authors.affiliation: Department of Molecular Genetics and Microbiology, Center for Virology, Duke University School of Medicine, Durham, NC 27712, USA.
authors.forename: Pavel A
authors.initials: PA
authors.lastname: Nikitin
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Yan
authors.forename: Eleonora
authors.initials: E
authors.lastname: Forte
authors.forename: Alessio
authors.initials: A
authors.lastname: Bocedi
authors.forename: Jason P
authors.initials: JP
authors.lastname: Tourigny
authors.forename: Robert E
authors.initials: RE
authors.lastname: White
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Allday
authors.forename: Amee
authors.initials: A
authors.lastname: Patel
authors.forename: Sandeep S
authors.initials: SS
authors.lastname: Dave
authors.forename: William
authors.initials: W
authors.lastname: Kim
authors.forename: Katherine
authors.initials: K
authors.lastname: Hu
authors.forename: Jing
authors.initials: J
authors.lastname: Guo
authors.forename: David
authors.initials: D
authors.lastname: Tainter
authors.forename: Elena
authors.initials: E
authors.lastname: Rusyn
authors.forename: Micah A
authors.initials: MA
authors.lastname: Luftig
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D001402:B-Lymphocytes / Q000473:pathology / Q000821:virology*; D018797:Cell Cycle Proteins / Q000502:physiology*; D049109:Cell Proliferation; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D064447:Checkpoint Kinase 2; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000502:physiology*; D019309:Epstein-Barr Virus Nuclear Antigens / Q000502:physiology; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D019309:Epstein-Barr Virus Nuclear Antigens; D025521:Tumor Suppressor Proteins; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases