EBV Modulation of Genome Stability in B-cell Lymphoma
openNCI - National Cancer Institute
Project Summary
Epstein-Barr Virus (EBV) is etiologically linked to multiple aggressive B cell malignancies, including
Burkitt lymphoma (BL), diffuse large B cell lymphoma (DLBCL), and post-transplant lymphoproliferative
disease (PTLD). These lymphomas arise from germinal center B cells, where antibody diversification
introduces uracils into DNA through activation-induced cytidine deaminase (AID). Under normal conditions,
base excision repair (BER) and mismatch repair (MMR) resolve these lesions to maintain genome stability.
However, persistent uracils promote mutations and chromosomal alterations that contribute to malignant
transformation. Re-analysis of EBV-positive BL tumor sequencing reveals mutational signatures consistent
with defects in both BER and MMR, suggesting that EBV may suppress uracil repair to promote
lymphomagenesis while protecting its own viral genome. While EBV's effects on DNA damage signaling have
been studied, its direct impact on uracil processing remains poorly understood.
This K99/R00 proposal outlines a transition plan for Dr. Jessica Stewart to define how EBV suppresses
uracil excision, alters DNA repair pathway utilization, and promotes mutagenesis. In the mentored phase
(K99), she will (Aim 1) investigate how EBV suppresses uracil excision and identify viral gene products that
impair uracil repair, and (Aim 2) dissect the function of FAM72A—a host factor upregulated by EBV that
antagonizes nuclear uracil glycosylase UNG2—through structural studies, interactome mapping, and small-
molecule screening. In the independent phase (R00), she will (Aim 3) define how unresolved uracils alter DNA
repair pathway usage and identify repair vulnerabilities that support EBV-driven B cell transformation.
Dr. Stewart's long-term goal is to establish an independent research program focused on how
oncogenic viruses reshape host DNA repair networks to drive malignant transformation. Building on her
expertise in uracil biochemistry and DNA repair, she will receive advanced training in viral recombination,
structural biology, repair pathway analysis, and in vivo modeling of EBV-associated tumors under the
mentorship of a multidisciplinary advisory committee with expertise in virology, DNA repair, and cancer biology.
The outstanding research environment at UNC Lineberger Comprehensive Cancer Center will provide the
resources, collaborations, and professional development needed to support her transition to independence.
This work aligns with NCI's mission to define cancer mechanisms and inform therapeutic strategies for virus-
associated malignancies.
Up to $117K
health research