# Mechanism of transcription-associated genome instability

> **NIH NIH R35** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2022 · $387,142

## Abstract

PROJECT SUMMARY: Changes in the genome such as mutagenesis, duplication, deletions, and
recombination bring about somatic diseases like cancer and drive evolutionary processes. My lab has been
focused on understanding how such genome instability events occur at incongruently higher frequencies at
certain “hotspots.” Quite different from the familiar depiction of chromosomes as stationary strings made up of
DNA, genome is more like a busy highway, where many proteins, including topoisomerases in surveillance for
irregular helical torsion, bind and/or actively modify DNA. Moreover, mega-complexes of proteins like RNA
polymerase and DNA polymerase complexes are dynamically moving along, unwinding, and forcibly distorting
DNA while carrying out transcription and replication, sometimes physically colliding with each other. In order to
explain why mutation/recombination hotspots are often located within actively transcribed regions, we viewed
the multiple DNA-involving processes as an interactive system rather than as each independent activity and
identified transcription-associated causes of genome instability. My work was instrumental in showing that
mutations resulting from the non-canonical residues, uracil and ribonucleotide, are highly elevated upon
transcription activation. Subsequently, novel discoveries in my lab led to the model that non-replicative DNA
synthesis occurring in G1- and G2-phases of the cell cycles results in higher uracil density in actively
transcribed genes. We also made key findings linking the transcription-generated negative torsional stress with
the elevated recombination associated with the DNA secondary structure G-quadruplex or G4 DNA. We further
identified G4 DNA-binding proteins that either suppress or exacerbate such G4 DNA-induced genome
instability. The central goal of my research program is to uncover fundamental and conserved mechanism
underlying mutagenesis and genome rearrangements, which will be important for both the cellular
transformation into cancers and responses to chemotherapeutics. Building upon our previous findings, we will
continue to address important remaining questions by (1) using tractable genetic approaches to study
transcription-associated genome instability in the simple eukaryotic model organism Saccharomyces
cerevisiae, (2) developing innovative approaches to test the model of uracil/ribonucleotide incorporation into
DNA during G1 and G2, and (3) defining the functional and structural interaction between key G4 DNA-binding
proteins and G4 DNA both in vitro and in vivo.
 Our ongoing investigation should further the understanding of how transcription, replication, and DNA
repair work in conjunction either for the benefit or the detriment of genome integrity. Having a comprehensive
picture of these interconnected and dynamic processes occurring on the genome will help in predicting how to
suppress and correct genome instability events adverse to normal cellular functions.

## Key facts

- **NIH application ID:** 10474278
- **Project number:** 5R35GM141867-02
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Nayun Kim
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $387,142
- **Award type:** 5
- **Project period:** 2021-09-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10474278

## Citation

> US National Institutes of Health, RePORTER application 10474278, Mechanism of transcription-associated genome instability (5R35GM141867-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10474278. Licensed CC0.

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