# Repair of Genome Destabilizing DNA Structures

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2020 · $328,359

## Abstract

PROJECT SUMMARY
Aging and cancer are inextricably linked. Genome instability is common to both aging and cancer, whereby
genetic instability and cancer risk increase with age. However, there is a fundamental gap in understanding the
mechanisms that predispose us to increased genetic instability as we age. Thus, the overall objective of this
application is to fill this gap in knowledge. Mutations are not random, and there are endogenous mutation
“hotspot” regions of the genome. Importantly, many of these cancer-assoicated mutation hotspots co-localize
with, and are enriched at sequences capable of adopting alternatively structured DNA (i.e. non-B DNA),
implicating these sequences in cancer etiology. We have discovered that naturally occurring non-B DNA; e.g.,
Z-DNA and H-DNA, is mutagenic in mammals, and this DNA structure-induced mutation increases with age.
However, the mechanisms involved in the age-related propagation of genetic instability at these hotspots are
unclear. Thus, a goal is to determine the mechanisms involved in DNA structure-induced genetic instability,
and the impact of increased age on the generation of these endogenous mutation hotspots. We have also
found that non-B DNA is processed by DNA repair and replication proteins. These findings provide the basis
for the scientific premise going forward to test the novel hypothesis that cancer relevant DNA structure-induced
genetic instability increases with age, because with age, non-B DNA (i.e. an endogenous mutation hotspot)
becomes increasingly refractory to repair; moreover, non-B DNA is subject to error-prone processing that
increases with age. Both mechanisms lead to the generation of age-dependent mutations. The long-term goals
are to elucidate the impact of aging on genetic instability at mutation hotspots, to determine the mechanisms of
age-related, and tissue-specific DNA structure-induced genetic instability in cancer etiology, and to develop
novel approaches to reduce genetic instability to prevent and/or treat age-related disease. The objectives are
to determine the role(s) of age in DNA structure-induced genomic instability in specific tissues of mice, and to
identify the mechanisms of replication-dependent and -independent genetic instability. We will use novel
mutation-reporter mice that we have developed to determine the effects of age on the mutagenic potential of
non-B DNA sequences, and determine the mechanisms of the processing of these mutagenic sequences. This
is innovative because it will test the novel hypothesis that DNA structure-induced genetic instability increases
with age in mammals, and that these structure-forming sequences are processed by DNA repair mechanisms
whose efficiency decline with age. The expected contribution is the elucidation of the impact of age on genetic
instability and of the mechanisms involved in the generation of endogeous mutation hotspots in cancer, to
provide a better understanding of age-related disease etiology. This is sig...

## Key facts

- **NIH application ID:** 9838724
- **Project number:** 5R01CA093729-19
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Karen M Vasquez
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $328,359
- **Award type:** 5
- **Project period:** 2002-01-28 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838724

## Citation

> US National Institutes of Health, RePORTER application 9838724, Repair of Genome Destabilizing DNA Structures (5R01CA093729-19). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9838724. Licensed CC0.

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