# Linking defects in DNA polymerase beta to mitochondrial dysfunction and cytosolic nucleic acid sensor in Helicobacter pylori associated inflammation

> **NIH NIH R01** · HOWARD UNIVERSITY · 2024 · $428,223

## Abstract

Project Summary
Targeting mitochondria has emerged as a key strategy for bacteria to hijack host cell physiology and
promote infection. Mitochondrial dysfunction shapes innate immune response and promotes inflammatory
responses. Several studies have shown that defective oxidative DNA damage repair pathways are associated
with mitochondrial dysfunction and chronic inflammatory diseases. Base excision repair (BER) is the
predominant pathway that corrects small base lesions caused by reactive oxygen and nitrogen species
(RONS).
BER is the major pathway for the repair of oxidative DNA lesions and is present in both nucleus and
mitochondria by similar mechanisms that share many of the core BER enzymes. DNA polymerase beta
(POLB) and gamma (POLG) are involved in maintenance of mitochondrial DNA (mtDNA) integrity. The 5’-
deoxyribophosphodiesterase (5’-dRP lyase) functions of POLB is more active than POLG 5’-dRP lyase
function to remove the 5’-dexyribose phosphate group (5’-dRP). In addition, we characterized 5’-dRP lyase
deficient POLB (L22P point mutation)] that results in loss of 5’-dRP lyase function as a model to examine
whether absence of 5’-dRP lyase impairs mitochondrial function and contributes to aberrant inflammatory
response. Our preliminary data show that BER deficient cells significantly accumulate mitochondrial DNA
(mtDNA) damage. Moreover, we found that Helicobacter pylori (H. pylori) infection exacerbates DNA damage
and inflammatory response in 5’-dRP lyase deficient mice. However, there are no data to explain how the BER
defect (
5’-dRP lyase deficient POLB) influences mitochondrial DNA mediated innate immune response and its
potential impact on induction of inflammation associated human diseases. In this application, we will examine
how defective BER associated mitochondrial dysfunction contributes to cytosolic nucleic acid sensor mediated
innate immune inflammatory response. Based on our highly significant and encouraging preliminary findings,
we will test the hypothesis that defective BER promotes mitochondrial dysfunction and provokes
cytosolic nucleic acid mediated signaling in H. pylori associated inflammation. In this study, we propose
three specific aims as follows: i) Determine whether BER deficient cells release mtDNA in the cytoplasm; ii)
Determine whether aberrant repair of mtDNA modulates
innate immune signaling in vitro and in vivo; and iii)
Define how the effects of aberrant BER (5’-dRP lyase deficient POLB) with H. pylori infection contribute to
cytosolic nucleic acid sensor mediated innate immune signaling and inflammatory response. Completion of the
proposed studies will provide novel mechanistic insight into how impaired mtBER and extracellular bacterial
infection contribute to mitochondrial dysfunction related inflammation. Further, unlocking cytosolic surveillance
and signaling upon extracellular bacterial infection may reveal new opportunities for future immune based
therapeutic strategy.

## Key facts

- **NIH application ID:** 10777284
- **Project number:** 1R01AI179899-01
- **Recipient organization:** HOWARD UNIVERSITY
- **Principal Investigator:** Dawit Kidane Mulat
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $428,223
- **Award type:** 1
- **Project period:** 2023-12-08 → 2028-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10777284

## Citation

> US National Institutes of Health, RePORTER application 10777284, Linking defects in DNA polymerase beta to mitochondrial dysfunction and cytosolic nucleic acid sensor in Helicobacter pylori associated inflammation (1R01AI179899-01). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10777284. Licensed CC0.

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