# The Role of Base Excision Repair in Regulating DNA-Mediated Inflammatory Signaling Pathways

> **NIH NIH R21** · HOWARD UNIVERSITY · 2021 · $182,409

## Abstract

PROJECT SUMMARY
 Defects in DNA repair underlie a number of human genetic diseases that affect a wide variety of
physiological systems and cause adverse phenotypes such as accelerated aging and predisposition to cancer.
Faithful DNA repair is necessary to maintain genomic integrity and prevent cancer. The base excision repair
(BER) pathway is responsible for repairing at least 20,000 lesions per cell per day. If left unrepaired, the
lesions can give rise to genomic instability and tumorigenesis. BER is also the major repair pathway for
nonbulky damaged bases, abasic sites, and DNA single-strand breaks after treatment with different DNA-
damaging agents. Several genes are involved in BER pathways, including DNA glycosylase, XRCC1, DNA
polymerase beta (Polβ), DNA ligase III, flap endonuclease 1 (FEN1), and DNA ligase I. BER deficiency can
lead to accumulated unrepaired DNA damage, generating cytosolic DNA that likely activates DNA-dependent
innate immune pathways. Cyclic GMP-AMP synthase (cGAS) is a key cytosolic DNA sensor that produces the
cyclic dinucleotide cGMP-AMP (cGAMP) upon activation, which triggers the activation of stimulator of
interferon genes (STING), leading to type I Interferon production. However, how deficiency in BER promotes
cGAS/STING-mediated inflammation is not yet fully understood. The goal of this exploratory R21 proposal is to
uncover how spontaneous DNA damage and failed BER stimulate host inflammatory response. We recently
developed a novel mouse model using a human genetic variant, which we will use to elucidate the molecular
mechanism of inflammation. Using a Cre-flox targeting system, we constructed an L22P conditional knock-in
mouse model that lacks dRP lyase function expressed at Rosa26a locus and cannot support BER. Our
preliminary data revealed that BER deficiency in our mouse model markedly induces genomic instability and
chronic inflammation. Thus, we hypothesize that BER deficiency accumulates cytosolic DNA that derives from
spontaneous DNA damage, thereby triggering the innate immune response.
In this study, we propose two
Specific Aims: (1) Determine the molecular mechanisms through which aberrant BER induces inflammation.
Using BER-deficient cells (
Polβ -/-; XRCC1; PARP1-/-; L22P (dRP lyase-deficient
Polβ), we will study how
BER deficiency triggers innate immune response-mediated inflammation. (2) Determine whether failed BER
stimulates cGAS/STING-mediated inflammation in mice. Using in vitro and in vivo models (L22P mouse
models), we will examine how cytosolic DNA-sensing pathways trigger inflammatory immune responses. The
outcomes of this study will define a novel paradigm for how aberrant BER induces the innate immune system,
and will have broad implications for the molecular mechanisms behind cGAS/STING function, as well as for
future immune-directed cancer therapies.

## Key facts

- **NIH application ID:** 10845149
- **Project number:** 7R21CA249346-02
- **Recipient organization:** HOWARD UNIVERSITY
- **Principal Investigator:** Dawit Kidane Mulat
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $182,409
- **Award type:** 7
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10845149

## Citation

> US National Institutes of Health, RePORTER application 10845149, The Role of Base Excision Repair in Regulating DNA-Mediated Inflammatory Signaling Pathways (7R21CA249346-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10845149. Licensed CC0.

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