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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Nikitin, PA; Yan, CM; Forte, E; Bocedi, A; Tourigny, JP; White, RE; Allday, MJ; Patel, A; Dave, SS; Kim, W; Hu, K; Guo, J; Tainter, D; Rusyn, E; Luftig, MA

Published Date

  • December 16, 2010

Published In

Volume / Issue

  • 8 / 6

Start / End Page

  • 510 - 522

PubMed ID

  • 21147465

Pubmed Central ID

  • PMC3049316

Electronic International Standard Serial Number (EISSN)

  • 1934-6069

Digital Object Identifier (DOI)

  • 10.1016/j.chom.2010.11.004


  • eng

Conference Location

  • United States