# MOLECULAR MECHANISMS OF STRESS-INDUCED MUTATION

> **NIH NIH R35** · BAYLOR COLLEGE OF MEDICINE · 2020 · $507,827

## Abstract

Genomic instability drives cancers, adaptation of pathogens to hosts, and evolution of resistance to anti-
pathogen and anti-cancer drugs. In contrast with classical assumptions that mutations occur purely
stochastically with constant and gradual rates, microbes, plants, flies and human cancer cells possess
mechanisms of mutagenesis upregulated by stress responses. Discovered in bacteria and similar across the
tree of life, these mechanisms generate transient bursts of genetic diversity that can propel evolution
specifically when cells are poorly adapted to their environments—when stressed. Stress-induced-mutation
mechanisms may provide superior models for genetic changes that drive pathogen-host adaptation, antibiotic
resistance, aging, cancer progression and therapy-resistance mechanisms, and possibly much of evolution
generally. This proposal addresses how stress responses upregulate mutagenesis, and how to stop them:
fundamental and medically urgent problems. We propose to investigate two stress-induced-mutation
mechanisms in E. coli: mutagenic DNA break repair (MBR), and mutagenesis induced by antibiotics: models
for mutagenesis in many medically critical contexts. Both require the general, stringent, and DNA-damage
stress responses, which allow error-prone DNA polymerases to promote mutations. Our approach will integrate
experimental genomic, genetic, synthetic and single-cell strategies with engineered proteins that trap DNA
reaction intermediates, all in living cells. We will address regulated mutagenesis from four directions:
· Discovery of how cells regulate MBR in time. Which gene(s) up- or down-regulated by the general
 stress-response throw the switch to mutagenic break repair? By what mechanism? How does the stringent
 stress response independently promote starvation- and antibiotic-induced MBR?
· Discovery of MBR regulation in single cells. Four stress responses promote MBR, some activated in
 cell subpopulations. We will determine which subpopulations undergo mutagenesis and illuminate
 differentiation into a mutable state—a possible evolutionary “bet hedging” strategy.
· Discovery of how cells restrict mutations in genomic space. We will map spontaneous DNA breaks in
 genomes, and unravel their causes. We will discover whether more breaks, more break-repair, or other
 causes target specific large genomic regions for multiple mutation hotspots.
· Antibiotic-induced mutagenesis. We will dissect a molecular mechanism of antibiotic-induced
 mutagenesis similar to MBR. We will develop novel drugs to target mutagenesis as possible antibiotic
 adjuncts, to slow evolution of pathogens, and as a model anti-cancer strategy.
This project includes collaborations with pioneering chemists, physicists, bioinformaticians, biochemists, and
molecular biologists. Our shared goal is to provide both important models for understanding of and
intervention in the medical problems listed above and specific tools for combating antibiotic resistance.

## Key facts

- **NIH application ID:** 9986774
- **Project number:** 5R35GM122598-04
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Susan M Rosenberg
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $507,827
- **Award type:** 5
- **Project period:** 2017-08-01 → 2020-09-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986774

## Citation

> US National Institutes of Health, RePORTER application 9986774, MOLECULAR MECHANISMS OF STRESS-INDUCED MUTATION (5R35GM122598-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9986774. Licensed CC0.

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