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Signal-induced PARP1-Erk synergism mediates IEG expression.

ABSTRACT: A recently disclosed Erk-induced PARP1 activation mechanism mediates the expression of immediate early genes (IEGs) in response to a variety of extra- and intracellular signals implicated in memory acquisition, development and proliferation. Here, we review this mechanism, which is initiated by stimulation-induced binding of PARP1 to phosphorylated Erk translocated into the nucleus. This binding maintains long-lasting synergistic activity of these proteins, which offers a new pattern for targeted therapy.

SUBMITTER: Cohen-Armon M

PROVIDER: S-EPMC6459926 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Signal-induced PARP1-Erk synergism mediates IEG expression.

Cohen-Armon Malka M Yeheskel Adva A Pascal John M JM

Signal transduction and targeted therapy 20190412

A recently disclosed Erk-induced PARP1 activation mechanism mediates the expression of immediate early genes (IEGs) in response to a variety of extra- and intracellular signals implicated in memory acquisition, development and proliferation. Here, we review this mechanism, which is initiated by stimulation-induced binding of PARP1 to phosphorylated Erk translocated into the nucleus. This binding maintains long-lasting synergistic activity of these proteins, which offers a new pattern for targete ...[more]

PMID: 30993015

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Project description:UnlabelledThe 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.ImportanceEBV 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.

Dataset Information

Signal-induced PARP1-Erk synergism mediates IEG expression.

Publications

Signal-induced PARP1-Erk synergism mediates IEG expression.

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