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

Pavel A. Nikitin, Christopher M. Yan, Eleonora Forte, Alessio Bocedi, Jason P. Tourigny, Robert E. White, Martin J. Allday, Amee Patel, Sandeep S. Dave, William Kim, Katherine Hu, Jing Guo, David Tainter, Elena Rusyn, Micah A. Luftig

Research output: Contribution to journalArticle

138 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)510-522
Number of pages13
JournalCell Host and Microbe
Volume8
Issue number6
DOIs
StatePublished - Dec 16 2010
Externally publishedYes

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Human Herpesvirus 4
DNA Damage
B-Lymphocytes
Virus Latency
Neoplasms
Herpesviridae
Oncogene Proteins
Cell Division
Carcinogenesis
Plasmids
Phosphotransferases
Cell Line
Growth

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

Cite this

An ATM/Chk2-mediated DNA damage-responsive signaling pathway suppresses Epstein-Barr virus transformation of primary human B cells. / Nikitin, Pavel A.; Yan, Christopher M.; Forte, Eleonora; Bocedi, Alessio; Tourigny, Jason P.; White, Robert E.; Allday, Martin J.; Patel, Amee; Dave, Sandeep S.; Kim, William; Hu, Katherine; Guo, Jing; Tainter, David; Rusyn, Elena; Luftig, Micah A.

In: Cell Host and Microbe, Vol. 8, No. 6, 16.12.2010, p. 510-522.

Research output: Contribution to journalArticle

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 2010, 'An ATM/Chk2-mediated DNA damage-responsive signaling pathway suppresses Epstein-Barr virus transformation of primary human B cells', Cell Host and Microbe, vol. 8, no. 6, pp. 510-522. https://doi.org/10.1016/j.chom.2010.11.004
Nikitin, Pavel A. ; Yan, Christopher M. ; Forte, Eleonora ; Bocedi, Alessio ; Tourigny, Jason P. ; White, Robert E. ; Allday, Martin J. ; Patel, Amee ; Dave, Sandeep S. ; Kim, William ; Hu, Katherine ; Guo, Jing ; Tainter, David ; Rusyn, Elena ; Luftig, Micah A. / An ATM/Chk2-mediated DNA damage-responsive signaling pathway suppresses Epstein-Barr virus transformation of primary human B cells. In: Cell Host and Microbe. 2010 ; Vol. 8, No. 6. pp. 510-522.
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