# Molecular Mechanisms of Replication Stress Response

> **NIH NIH R35** · UNIVERSITY OF SOUTH FLORIDA · 2020 · $347,014

## Abstract

PROJECT SUMMARY
DNA replication is accomplished by highly regulated macromolecular complexes called
replisomes. Numerous challenges such as damaged DNA templates, repetitive sequences, and
transcriptional complexes hinder DNA replication and stall replication forks. Stalled forks activate
the replication stress response to signal repair of damaged DNA, recruit proteins, and halt cell
cycle; thereby stabilizing replication forks and preventing collapse into toxic double strand breaks.
Failure to deal with replication stress can cause diseases characterized by abnormal
development, accelerated aging and cancer predisposition. For these reasons, it is critical to
understand genome maintenance pathways that promote accurate DNA replication in the context
of replication stress. To gain further mechanistic insight into replication stress response pathways,
I previously developed a quantitative proteomic screening approach to study the protein
composition of replisomes at unperturbed and stalled replication forks in human cells. This work
provides evidence for checkpoint-independent replisome stabilization, a model contrary to
prevailing models of replisome dissociation when checkpoint is inhibited, as well as mechanistic
insights into ATR inhibitors that are currently utilized in clinical trials as chemotherapeutics. I also
generated comprehensive proteomic datasets of active, stalled, and collapsed replication forks.
These datasets include potential regulators of replication stress response, and also identifies
mediators of replication fork protection, which is relevant to acquired chemoresistance in breast
cancers. My lab will utilize this vast resource in combination with detailed functional studies to
reveal previously unknown genome maintenance mechanisms. The proposed research program
is designed to address three key areas in my lab: 1) Characterization of new replication stress
response proteins, 2) Replication fork protection in breast cancers, and 3) Regulation of
replication stress response by phosphorylation.
 Completion of these goals will reveal new fundamental insights into the molecular
mechanisms of replication stress response that can lead to paradigm-shifting discoveries thereby
expanding our view on genome maintenance mechanisms that govern DNA replication and
providing avenues for designing effective treatments in cancer chemotherapy.

## Key facts

- **NIH application ID:** 10025867
- **Project number:** 1R35GM137800-01
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** Huzefa Mannan Dungrawala
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $347,014
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10025867

## Citation

> US National Institutes of Health, RePORTER application 10025867, Molecular Mechanisms of Replication Stress Response (1R35GM137800-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10025867. Licensed CC0.

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