# Replication fork protection and innate immune response

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $340,200

## Abstract

ABSTRACT
Protection of stalled replication forks is crucial for cells to respond to replication stress and maintain genome
stability. Recent research has provided strong evidences that genome instability can trigger inflammatory
response when chromosomal or short stranded nuclear DNA are released into the cytoplasm and detected by
a cytosolic DNA sensing pathway, the cGAS-STING-dependent pathway. Emerging evidences indicate that
DNA repair or replication fork processing in the replication stress response is connected with activation of the
innate immune response. However, much remains unknown about the link between stalled replication fork
protection and innate immune response. In addition, the physiological consequence of replication stress-
induced innate immune response in vivo remains to be defined. Our recent study reveals a role of Abro1 and
FANCD2 in linking replication fork protection with restriction of innate immune response. We found that stalled
replication fork degradation induced by Abro1- or FANCD2-deficiency leads to accumulation of cytosolic single-
stranded DNA (ssDNA) and activation of cGAS-STING-dependent innate immune signaling. Increased
cytosolic ssDNA including ribosomal DNA (rDNA) binds to cGAS activating cGAS-dependent innate immune
signaling and secretion of proinflammatory cytokines/chemokines. In addition, Abro1 and FANCD2 limits
replication stress-induced Processing bodies (P-bodies) formation and P-bodies are capable of modulating
activation of the innate immune signaling upon replication stress. We propose to determine the underlying
mechanism by which replication fork protection limits the induction of innate immune response and define fork
degradation-induced innate immune response in vivo. We will carry out the following specific aims: (1) to
delineate stalled fork degradation-induced activation of innate immune signaling; (2) to determine the
involvement of P-bodies in stalled fork degradation-induced activation of innate immune signaling; (3) to
determine the physiological effect of Abro1 deficiency-induced replication fork degradation associated
secretory phenotype in vivo in mice. Overall, this project will provide novel insights into the link of replication
fork protection and innate immune response, contributing to establishing new possibilities for the treatment of
inflammatory disorders and cancer in the future.

## Key facts

- **NIH application ID:** 10980646
- **Project number:** 1R01GM152613-01A1
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Bin Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $340,200
- **Award type:** 1
- **Project period:** 2024-09-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10980646

## Citation

> US National Institutes of Health, RePORTER application 10980646, Replication fork protection and innate immune response (1R01GM152613-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10980646. Licensed CC0.

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