EBV Conference 2008 Guangzhou - Baylor College of Medicine

66 (RegID: 1395)
Micah Luftig
Institution: Duke University
e-mail: micah.luftig@duke.edu
EBV INDUCES AN ATM AND CHK2-DEPENDENT DNA DAMAGE RESPONSIVE PATHWAY
EARLY AFTER INFECTION THAT LIMITS B CELL PROLIFERATION AND LONG-TERM
LCL OUTGROWTH
Micah Luftig, Eleonora Forte, Olena Rusyn, Pavel Nikitin, Chris Yan, David Tainter, Jing Guo
Posterabstract:
Epstein-Barr virus infection of primary B cells leads to long-term outgrowth of less than 10% of infected
cells. As such, a robust innate tumor suppressor response likely exists in more than 90% of infected cells
preventing outgrowth. Recently, the DNA damage response (DDR) to oncogene-induced replicative stress
has been shown to suppress proliferation acting as an early barrier to tumorigenesis through inducing
senescence and apoptosis. We therefore asked whether EBV infection of primary B cells activated the
DNA damage response and what the functional consequence of this response was on long-term LCL
outgrowth. We found that within two days of infection, EBV induced a robust DDR as determined by
phosphorylation of key checkpoint kinases ATM and Chk2, the ATM-specific phosphorylation of p53, and
the accumulation of DDR components, including 53BP1, to intra-nuclear foci. These activations were
dependent on latency III gene expression as P3HR1 and UV-inactivated B95-8 infected cells did not
induce these events. Importantly, inhibition of the DNA damage sensing kinase ATM or its downstream
effector Chk2 led to a 5-10 fold increase in EBV transformation efficiency as well as the increased
proliferation of B cells within the first two weeks following infection. Thus, EBV latency III gene
expression, likely through the induction of Myc activity early after infection, upregulates a DNA damage
responsive pathway that limits transformation. The significance of these activations in the context of
oncogenic stress and DNA damage pathways will be discussed.
EBV Conference 2008 Guangzhou
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