# Properties and Mechanisms of Punctuated Genome Instability

> **NIH NIH K99** · COLORADO STATE UNIVERSITY · 2022 · $33,333

## Abstract

Project Summary: Destabilization of the genome is known to cause and perpetuate many diseases, particularly
cancer. Normally, genome stability is maintained by numerous cellular processes devoted to preserving and
repairing DNA. As a result, cells rarely acquire new mutations. However, recent findings from our group and
others have demonstrated that cells can undergo transient episodes of genome destabilization and acquire
numerous genomic mutations simultaneously. These events, termed saltational bursts of genomic instability,
drive rapid genome evolution and are posited to contribute to the initiation and progression of multiple types of
cancer. Currently, we understand very little about the properties and causes of saltational bursts, largely because
a model system with which to rigorously study these events has been lacking. We have recently characterized
bursts of genomic instability in the budding yeast Saccharomyces cerevisiae. Based on compelling preliminary
data, we hypothesize that stochastic failures in genome maintenance can cause saltational bursts of genomic
instability and lead to transient mutagenic episodes. In this application, I propose to use innovative genomic and
cellular approaches to comprehensively explore key attributes of saltational bursts of mutagenesis. Specifically,
I will 1) investigate the temporal properties of bursts in order to define the duration of these destabilizing
episodes, 2) determine whether bursts occur through defects in specific genome integrity pathways, and 3)
determine how variable activity of these pathways modulates the frequency and mutational load of saltational
bursts. By conducting the above studies, I will contribute much needed insight into the mutational mechanisms
that drive rapid evolution. Moreover, these studies will strengthen our understanding of the mutagenic events
that give rise to diseases.

## Key facts

- **NIH application ID:** 10582452
- **Project number:** 3K99GM134193-02S1
- **Recipient organization:** COLORADO STATE UNIVERSITY
- **Principal Investigator:** Lydia Rene Heasley
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $33,333
- **Award type:** 3
- **Project period:** 2020-04-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10582452

## Citation

> US National Institutes of Health, RePORTER application 10582452, Properties and Mechanisms of Punctuated Genome Instability (3K99GM134193-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10582452. Licensed CC0.

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