An ATM/Chk2-mediated DNA damage-responsive signaling pathway suppresses Epstein-Barr virus transformation of primary human B cells

Cell Host Microbe. 2010 Dec 16;8(6):510-22. doi: 10.1016/j.chom.2010.11.004.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia Mutated Proteins
  • B-Lymphocytes / pathology
  • B-Lymphocytes / virology*
  • Cell Cycle Proteins / physiology*
  • Cell Proliferation
  • Cell Transformation, Viral
  • Cells, Cultured
  • Checkpoint Kinase 2
  • DNA Damage*
  • DNA-Binding Proteins / physiology*
  • Epstein-Barr Virus Nuclear Antigens / physiology
  • Herpesvirus 4, Human / physiology*
  • Humans
  • Protein-Serine-Threonine Kinases / physiology*
  • Signal Transduction
  • Tumor Suppressor Proteins / physiology*

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Epstein-Barr Virus Nuclear Antigens
  • Tumor Suppressor Proteins
  • Checkpoint Kinase 2
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK2 protein, human
  • Protein-Serine-Threonine Kinases

Associated data

  • GEO/GSE20200