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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

Date

12/15/2010

Pubmed ID

21147465

Pubmed Central ID

PMC3049316

DOI

10.1016/j.chom.2010.11.004

Scopus ID

2-s2.0-78650217703 (requires institutional sign-in at Scopus site)   185 Citations

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.

Author List

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

Author

Katherine Hu MD Assistant Professor in the Surgery department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Ataxia Telangiectasia Mutated Proteins
B-Lymphocytes
Cell Cycle Proteins
Cell Proliferation
Cell Transformation, Viral
Cells, Cultured
Checkpoint Kinase 2
DNA Damage
DNA-Binding Proteins
Epstein-Barr Virus Nuclear Antigens
Herpesvirus 4, Human
Humans
Signal Transduction
Tumor Suppressor Proteins