# Uracil DNA Glycosylases in Gammaherpesvirus Pathogenesis and B Cell Development

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $485,503

## Abstract

Project Summary
Each herpesvirus encodes a viral homolog of mammalian uracil DNA glycosylase (vUNG). Mammalian UNG is
an enzyme that removes misincorporated and mutagenic uracils, leaving an abasic site typically repaired by
the host base excision repair pathways. Although there is conserved sequence and in vitro activity between
vUNG and host UNG, little is known regarding vUNG function in the virus lifecycle or effect on host genome
DNA repair. Studies indicate that herpesvirus vUNG may interact with components of the viral DNA replication
machinery; however, its role in late stage replication events in primary cells is uncertain. We utilize murine
gammaherpesvirus 68 (MHV68) as a mouse model for human gammaherpesviruses, Epstein-Barr virus and
Kaposi's sarcoma-associated herpesvirus. Our studies indicate that herpesvirus vUNG plays a critical role in
pathogenesis, as vUNG deficient virus has major replication and infectivity defects. Gammaherpesvirus infects
germinal center (GC) B cells and establishes latency in memory B cells, a process that can lead to
immortalization and transformation of B cells. In GC B cells, host UNG activity process AID induced uracils to
trigger antibody diversification, a process that also triggers chromosome translocations that are associated with
lymphomas. Our studies indicate vUNG can process uracil in genomic DNA but with repair outcome different
than host UNG. vUNG suppresses antibody mutation and class switch recombination in a manner that is both
catalytic and non-catalytic dependent suggesting a scaffold function for vUNG. Thus, vUNG has the potential
to contribute to altered viral pathogenesis, immunity and malignancy. We propose studies to understand how
vUNG promotes viral pathogenesis and subverts host antibody diversification. In Aim 1, the structural and
biochemical basis for error-free repair of DNA lesions by vUNG will be investigated. Differences between
vUNG and host UNG will be characterized to determine the domains and interacting partners that result in
differential error-free versus error-prone repair outcome. In Aim 2, the mechanisms by which vUNG promotes
gammaherpesvirus pathogenesis will be investigated. The contribution of vUNG enzymatic function and
scaffold functions will be characterized. In Aim 3, the impact of gammaherpesvirus infection and vUNG on B
cell development will be investigated. B cell activation and immunoglobulin repertoire will be examined during
MHV68 infection. Antibody repertoire and self-reactivity will be analyzed during acute infection and latency
reactivation. Our aims straddle molecular immunology and molecular virology in the fields of
gammaherpesvirus pathogenesis and B cell biology. The proposed studies should elucidate the mechanism by
which vUNG supports viral replication, infection, and viral subversion of immunoglobulin diversification.

## Key facts

- **NIH application ID:** 9932320
- **Project number:** 5R01AI125397-05
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Kevin Michael McBride
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $485,503
- **Award type:** 5
- **Project period:** 2016-06-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932320

## Citation

> US National Institutes of Health, RePORTER application 9932320, Uracil DNA Glycosylases in Gammaherpesvirus Pathogenesis and B Cell Development (5R01AI125397-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9932320. Licensed CC0.

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