# PARP1-Chromatin and NAD-Metabolism in EBV Epithelial Cancers

> **NIH NIH P01** · WISTAR INSTITUTE · 2024 · $447,159

## Abstract

PROJECT 2 – PROJECT SUMMARY
EBV(+) epithelial cancers represent 75% of all the EBV(+) malignancies. Despite the presence of virus infection,
these EBV(+) tumors receive the same treatment as EBV(-) cancers. The long-term goal of this Program Project
is to identify specific targetable mechanisms of EBV-mediated oncogenesis in epithelial cells. We previously
showed that EBV latency and oncogenicity are regulated by factors that link epigenetics with metabolism, such
Poly-ADP-ribose Polymerases (PARPs). Drugs that target PARPs have the potential to be effective therapeutic
options for EBV(+) tumors. However, our incomplete understanding of the epigenetic and metabolic mechanisms
regulating EBV latency in epithelial cells limits the application of such drug options to treat EBV(+) epithelial
malignancies.
In this project (Project 2), we investigated the role of PARP1 in regulating EBV genome maintenance, gene
expression, and metabolic sensing in epithelial cells. We found that PARP1 forms a complex with CTCF on the
EBV genome. We now show that this complex includes UHRF1, an epigenetic reader protein involved in DNA
methylation pattern propagation. We found that treatment of EBV(+) cells with PARP1 inhibitors disrupts this
complex altering both viral and cellular gene expression and causing global DNA hypomethylation. Consistently,
PARP inhibitors synergized with DNA hypomethylating agents to elicit cytotoxicity in EBV+ gastric cancers both
in vitro and in vivo. Based on these data, we hypothesize that in EBV+ epithelial cells, PARP1, by interacting
with CTCF and UHRF1 and modulating their functions, is a key epigenetic factor that connects 3D chromatin
conformation and DNA methylation to enable EBV latency and EBV-driven epithelial cell oncogenesis .We base
our hypothesis on our preliminary data showing that EBV+ epithelial cells hyper-activate PARP1 and that this
drives changes in the 3D conformation of the EBV genome supporting viral latent gene expression. We observed
that multiple mechanisms for hyper-activation of PARP1 exist in EBV+ cells, including regulation of the ERK/MEK
pathway. We observed that differences exist in NAD+/NADH ration between EBV+ and EBV- epithelial cells,
indicating that EBV+ cells are metabolically equipped to sustain PARP1 activation. This observation is consistent
with our observation that EBV+ cells are sensitive to inhibitors of NAD salvage pathways, indicating that NAD
metabolism plays a key and underappreciated role in EBV -driven oncogenesis in epithelial cancer cells.
Programmatic Interactions. This project is highly integrated with other projects and cores. Collaborations with
Project 1 on the effect of PARP1 and NAD metabolism on EBNA1 functions; and with Project 3 on the relevance
of the PARP1/CTCF/UHRF1 complex for CIMP reversal and PI3K blockade. We have engaged all three cores:
Core B for the development of novel small molecule PARP1 degraders, Core D for analysis of chromosome
conformations and gene regula...

## Key facts

- **NIH application ID:** 10840311
- **Project number:** 5P01CA269043-02
- **Recipient organization:** WISTAR INSTITUTE
- **Principal Investigator:** Italo Tempera
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $447,159
- **Award type:** 5
- **Project period:** 2023-05-11 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10840311

## Citation

> US National Institutes of Health, RePORTER application 10840311, PARP1-Chromatin and NAD-Metabolism in EBV Epithelial Cancers (5P01CA269043-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10840311. Licensed CC0.

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