# Defining how cellular DNA replication and repair machinery are hijacked by viral pathogens

> **NIH NIH R35** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $375,430

## Abstract

PROJECT SUMMARY / ABSTRACT
 Mammals have evolved an extensive nuclear network of DNA replication and repair proteins that are
tasked with amplifying and maintaining the fidelity of their genetic code. These signaling mechanisms are always
active, surveying the genome to maintain its integrity in the face of attack from external abiotic factors (such as
radiation and chemicals) and biotic factors (bacteria and viruses). To counter the sentinels of genome integrity,
viral pathogens have evolved strategies to usurp these host replication and repair proteins for their own benefit.
Viral strategies to hijack the nuclear compartment include: localizing to cellular sites of DNA damage, generating
additional DNA breaks on the host, amplifying the cellular DNA damage signals and tethering themselves extra-
chromosomally to DNA break sites to persist long-term. However, the mechanisms by which viruses carry out
these pathogenic activities remain largely unknown. Better mechanistic understanding of how viruses
dysregulate host DNA repair and replication pathways are essential for developing therapeutic interventions for
human health. The goal of this research program is to understand how genome stability is impacted by viral
pathogens by building on existing technologies to develop novel tools that will help us interrogate how replication
and repair proteins are usurped, modified and leveraged by DNA viruses. We propose to answer fundamental
questions about host genome stability that are utilized by viral pathogens for short-term and long-term benefit.
We will determine how cellular signals are modulated on a global scale by DNA viruses and how these signals
impact host replication proteins. We will then decipher how viruses utilize cellular signals to localize their proteins
and genomes to cellular DNA break sites. Lastly, we will interrogate how cellular proteins are used by viruses to
tether themselves in proximity to DNA break sites for long-term persistence. Not only are these fundamental
discoveries, they also have the potential to inform cancer therapies and human DNA repair in addition to
generating knowledge about viral life cycles. These basic studies on viruses and DNA damage will benefit a
diverse array of biologists who study viral signaling in the biosphere. These strong foundational methodologies
can be applied broadly to study all eukaryotic viruses as well as bacteriophages.

## Key facts

- **NIH application ID:** 10938632
- **Project number:** 1R35GM154938-01
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Kinjal Majumder
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $375,430
- **Award type:** 1
- **Project period:** 2024-09-10 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10938632

## Citation

> US National Institutes of Health, RePORTER application 10938632, Defining how cellular DNA replication and repair machinery are hijacked by viral pathogens (1R35GM154938-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10938632. Licensed CC0.

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