# How does a viral pathogen manipulate the DNA Damage Response to promote successful viral infection?

> **NIH NIH K99** · UNIVERSITY OF MISSOURI-COLUMBIA · 2020 · $19,832

## Abstract

SUMMARY
 DNA viruses elicit a cellular DNA damage response (DDR) in infected cells, either in response to
incoming viral genomes, or to the large number of foreign genomes generated during virus replication. The
DDR forms an innate, critical barrier that can impede or facilitate virus replication. Following host cell infection,
replication of the parvovirus minute virus of mice (MVM) induces a sustained DDR, which is then exploited to
enhance its replication.
 Parvovirinae, small non-enveloped icosahedral viruses, are important pathogens in many animal
species including humans. These are the only known viruses of vertebrates that contain single-stranded linear
DNA genomes, presenting novel replicative DNA structures to the host cell nucleus during infection while
relying on cellular processes to replicate. Recent studies by the Pintel lab has shown that MVM interacts with
sites of DNA damage to initiate and amplify its infection. This application proposes to examine how MVM
exploits the cellular DDR to prepare the nuclear environment for effective parvovirus takeover.
Aim 1: How does MVM initiate and activate the host cell’s DNA damage signaling pathway? MVM
infection recruits the cellular DDR sensor MRE11 in an MRN (MRE11-RAD50-NBS1) holocomplex-
independent manner, but activates a downstream ATM signaling cascade. This project will examine how
MRE11 localizes to MVM, and initiates a downstream DDR without its canonical intermediate adaptor complex.
Aim 2: How does MVM utilize DNA- and protein- bridging molecules to establish replication centers at
sites of DNA damage? MVM associates with cellular DDR sites bound by the architectural protein CTCF, and
the DDR-chromatin binding protein MDC1. This study will decipher the mechanism by which CTCF and MDC1
drive the formation of viral replication centers, and how they influence the cellular chromatin architecture.
Aim 3: Determine how MVM infection induces additional host-cell DNA damage. MVM infection leads to
the production of cellular reactive oxygen species (ROS), which contributes to cellular DNA damage. This
research will characterize how MVM induces ROS, and how it utilizes the resulting stress signals to amplify
downstream DDR signals, thereby expanding infection.
Characterization of the interaction between the incoming viral genome and cellular DDR sensors will provide
important insight into how cellular DDR cascades are initiated. Secondly, it will elucidate the mechanisms of
trans-interaction between MVM and host chromosome at sites of DNA damage. Finally, studies on ROS
induction will help in the understanding of how virus replication induces additional DNA breaks, allowing it to
expand further. Examining these processes will be essential for understanding how parvoviruses interact with
cells, how they program successful infection and ultimately how they cause disease or persist as gene therapy
vehicles. Findings from these studies will be extrapolatable to other DNA viruses and pathogeni...

## Key facts

- **NIH application ID:** 9870149
- **Project number:** 1K99AI148511-01
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** Kinjal Majumder
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $19,832
- **Award type:** 1
- **Project period:** 2020-07-15 → 2020-09-20

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9870149

## Citation

> US National Institutes of Health, RePORTER application 9870149, How does a viral pathogen manipulate the DNA Damage Response to promote successful viral infection? (1K99AI148511-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9870149. Licensed CC0.

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