# Repair of Genome Destabilizing DNA Structures

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2024 · $369,568

## Abstract

PROJECT SUMMARY
Cancer incidence increases with age in a tissue-specific fashion. Genetic instability and epigenetic alterations
(e.g., cytosine methylation) are hallmarks of both cancer etiology and aging, thus linking aging to cancer.
Importantly, alternative DNA structure-forming sequences (i.e., non-B DNA) have been identified as
endogenous mutation hotspots associated with cancer etiology in an age-related and tissue-specific fashion.
Further, methylation can impact non-B DNA formation, its mutagenic potential, and DNA repair mechanisms;
and the mutagenic processing of non-B DNA requires DNA repair proteins. However, the mechanisms involved
in the age-related and tissue-specific generation of these mutation “hotspots” remain largely unknown. With the
aging population increasing, there is a critical need to fill this fundamental gap in knowledge. Our long-term
goal is to elucidate the mechanisms of age-associated, tissue-specific DNA structure-induced genetic
instability to guide future studies to develop new strategies to prevent and/or treat cancer. Thus, the overall
objective of this application is to determine the mechanisms involved in differential DNA structure-induced
genetic instability with age and tissue type to inform on cancer etiology. We will test the novel hypothesis that
the formation of non-B DNA and their mutagenic processing differ with age in a tissue-specific fashion due to
alterations in DNA repair processing and cytosine methylation. The rationale is that determining the
mechanisms associated with age-related, tissue-specific DNA structure-induced genetic instability will offer a
novel scientific framework whereby new strategies to prevent and/or treat age-associated diseases, such as
cancer, can be developed. The hypothesis will be tested in the following aims: 1) Measure the amount of non-B
DNA formed and its mutagenic potential with age in mouse tissues; 2) determine age- and tissue-associated
alterations in cytosine methylation that alter non-B DNA structure formation and mutagenesis; and 3) identify
the DNA repair-associated mechanisms of mutagenic processing of endogenous mutation hotspots with age in
mice. Novel mutation-reporter mice containing human non-B DNA sequences from cancer-associated mutation
hotspots will be used to determine the effects of age and tissue type on the mutagenic processing of non-B
DNA. This is innovative because it will test the novel hypothesis that DNA structure-induced genetic instability
is altered with age and tissue type in mammals, dependent on age-related modulations in epigenetics and
DNA repair. The expected contribution is the elucidation of the impact of age and tissue type on DNA structure-
induced genetic instability, which is significant because the results will inform on the etiology of various cancer
types with age. This is expected to have a significant positive impact because the results will help achieve our
long-term goal to understand the mechanisms of age-associat...

## Key facts

- **NIH application ID:** 10770505
- **Project number:** 5R01CA093729-23
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Karen M Vasquez
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $369,568
- **Award type:** 5
- **Project period:** 2002-01-28 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10770505

## Citation

> US National Institutes of Health, RePORTER application 10770505, Repair of Genome Destabilizing DNA Structures (5R01CA093729-23). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10770505. Licensed CC0.

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