# Mechanisms of Obesity-Induced Genetic Instability at Endogenous Mutation Hotspots

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2020 · $435,807

## Abstract

PROJECT SUMMARY
The overall objective of this proposal is to understand how dietary energy balance and especially obesity
influences genome stability at endogenous mutation “hotspots”. To achieve this objective, we will use novel
mouse models that we have developed to determine the impact of obesity on DNA structure-induced
mutagenesis in various tissues from these mice. Repetitive DNA sequences are widely dispersed throughout
mammalian genomes and can adopt alternative (non-B DNA) secondary structures, such as H-DNA and Z-
DNA. Importantly, these non-B DNA structure-forming sequences are significantly enriched at endogenous
mutation hotspots in human cancer genomes, implicating them in cancer etiology. For example, H-DNA-
forming sequences in the c-MYC gene are found at translocation breakage hotspots in Burkitt’s lymphoma and
acute B-cell lymphoma. We have developed novel mutation-reporter mice containing human H-DNA- and Z-
DNA-forming sequences that co-localize with translocation breakpoint hotspots, and demonstrated for the first
time that these sequences are mutagenic in vivo. Obesity is known to increase cellular oxidative stress and
oxidative DNA damage, whereas calorie restriction has been shown to decrease cellular oxidative stress,
oxidative DNA damage, reduce mutagenesis and to enhance DNA repair pathways. In addition, obesity is an
important risk factor for a significant number of cancers. However, the extent to which dietary energy balance
and especially obesity influences DNA structure-induced genetic instability is not known. Thus, a goal of the
proposed work is to fill this gap in knowledge. In this proposal, we will test the working hypothesis that obesity
increases DNA structure-induced genetic instability. We will examine the impact of diet-induced obesity and
calorie restriction on DNA structure-induced mutagenesis in mice. Several different tissues will be evaluated
from these mice to determine whether there are any tissue specific differences in mutagenesis in response to
energy balance manipulation. We will also explore mechanisms for the impact of obesity on DNA structure-
induced genetic instability. We will focus our studies on the impact of obesity on DNA repair mechanisms as
several recent studies have suggested that obesity impairs multiple DNA repair pathways, including non-
homologous end-joining, a repair pathway that we have found to play a role in the processing of non-B DNA. In
addition, we have found that flap endonuclease 1 (FEN1) plays an important role in error-free processing of
non-B DNA and that its levels are modulated by dietary energy balance. These observations will also be
explored in more detail in this proposal. Completion of the proposed studies will lead to a greater
understanding of how obesity influences cancer etiology. In addition, this work will lead to the identification of
novel targets for the prevention and/or treatment of obesity-related cancers.

## Key facts

- **NIH application ID:** 9828085
- **Project number:** 5R01CA225029-03
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** John DiGiovanni
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $435,807
- **Award type:** 5
- **Project period:** 2018-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828085

## Citation

> US National Institutes of Health, RePORTER application 9828085, Mechanisms of Obesity-Induced Genetic Instability at Endogenous Mutation Hotspots (5R01CA225029-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9828085. Licensed CC0.

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