The latent infection of Epstein-Barr virus (EBV) is associated with 1% of human 
cancer incidence. Poly(ADP-ribosyl)ation (PARylation) is a posttranslational 
modification catalyzed by poly(ADP-ribose) polymerases (PARPs) that mediate EBV 
replication during latency. In this study, we detail the mechanisms that drive 
cellular PARylation during latent EBV infection and the effects of PARylation on 
host gene expression and cellular function. EBV-infected B cells had higher PAR 
levels than EBV-negative B cells. Moreover, cellular PAR levels were up to 
2-fold greater in type III than type I latently infected EBV B cells. We 
identified a positive association between expression of the EBV genome-encoded 
latency membrane protein 1 (LMP1) and PAR levels that was dependent upon PARP1. 
PARP1 regulates gene expression by numerous mechanisms, including modifying 
chromatin structure and altering the function of chromatin-modifying enzymes. 
Since LMP1 is essential in establishing EBV latency and promoting tumorigenesis, 
we explored the model that disruption in cellular PARylation, driven by LMP1 
expression, subsequently promotes epigenetic alterations to elicit changes in 
host gene expression. PARP1 inhibition resulted in the accumulation of the 
repressive histone mark H3K27me3 at a subset of LMP1-regulated genes. Inhibition 
of PARP1, or abrogation of PARP1 expression, also suppressed the expression of 
LMP1-activated genes and LMP1-mediated cellular transformation, demonstrating an 
essential role for PARP1 activity in LMP1-induced gene expression and cellular 
transformation associated with LMP1. In summary, we identified a novel mechanism 
by which LMP1 drives expression of host tumor-promoting genes by blocking 
generation of the inhibitory histone modification H3K27me3 through PARP1 
activation.
IMPORTANCE: EBV is causally linked to several malignancies and is responsible 
for 1% of cancer incidence worldwide. The EBV-encoded protein LMP1 is essential 
for promoting viral tumorigenesis by aberrant activation of several well-known 
intracellular signaling pathways. We have identified and defined an additional 
novel molecular mechanism by which LMP1 regulates the expression of 
tumor-promoting host genes. We found that LMP1 activates the cellular protein 
PARP1, leading to a decrease in a repressive histone modification, accompanied 
by induction in expression of multiple cancer-related genes. PARP1 inhibition or 
depletion led to a decrease in LMP1-induced cellular transformation. Therefore, 
targeting PARP1 activity may be an effective treatment for EBV-associated 
malignancies.