# Molecular mechanisms of sensing nuclear stress and launching antiviral defense by PML

> **NIH NIH R21** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2024 · $249,688

## Abstract

ABSTRACT
The human herpesviruses are responsible for lifelong debilitating and congenital infections, and some members
of this family are associated with human cancers. HSV causes significant disease during acute infection and
establishes persistent latent infections in sensory neurons for the life of the host leading to reactivation and
recurrent disease. This proposal is based on a series of observations about the interplay between HSV infection
and the intrinsically antiviral cellular protein, PML. In response to interferon treatment, oxidative stress, DNA
damage, and viral infection PML oligomerizes to form a mesh-like spherical shell around heterogeneous, phase-
separated nuclear condensates, called PML nuclear bodies (PML-NBs). PML oligomerization leads to the
activation of its SUMO ligase activity, which in turn induces the recruitment of dozens of cellular proteins that
contain SUMO-interacting motifs (SIMs) including repressors of gene expression into PML-NBs via SUMO/SIM
interactions. PML-NBs are anti-viral, however, the exact mechanism of their action remains poorly understood.
PML-NBs size and number increase in response to HSV infection, and they are actively targeted for degradation
by HSV1 as a mechanism to counteract their antiviral effects. During HSV infection PML-NBs have often been
observed adjacent to the sites of viral DNA replication and have recently been shown to entrap the entire viral
genome.
Despite a rudimentary understanding of these processes, many questions remain about how PML-NB formation
is triggered by HSV infection and how they are recruited to viral genomes. Oligomerization and sumoylation of
PML have been shown to be essential for the effective formation of PML-NBs in response to stress. In Aim 1
we will identify PML domains that are necessary for its SUMO-E3 ligase activity and required for
formation of the PML-NBs. One of the most surprising aspects of PML-NB formation is their ability to form
around and entrap viral DNA, resulting in genome silencing. The properties of PML that promote this unusual
ability to recognize viral DNA are not understood. In Aim 2 we will test the hypothesis that PML contains a
DNA-binding domain necessary for recruitment of PML-NBs to viral genomes. Together, these aims will
probe the fundamental mechanisms behind the two key events that trigger the formation of PML-NBs in
response to HSV infection.

## Key facts

- **NIH application ID:** 10988484
- **Project number:** 1R21AI178136-01A1
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Irina Bezsonova
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $249,688
- **Award type:** 1
- **Project period:** 2024-06-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10988484

## Citation

> US National Institutes of Health, RePORTER application 10988484, Molecular mechanisms of sensing nuclear stress and launching antiviral defense by PML (1R21AI178136-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10988484. Licensed CC0.

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