# The role of transcription factor proteins in mutagenesis at regulatory sites

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $336,835

## Abstract

ABSTRACT
More than 90% of cancer somatic mutations fall in non-coding regions of the genome. While the vast majority
of these mutations are expected to be passengers, a small fraction could act as drivers by disrupting regulatory
interactions between transcription factors (TFs) and DNA, leading to dysregulation of gene expression. Despite
the increased availability of whole-genome cancer somatic mutation data, identifying non-coding driver
mutations in TF binding sites remains a challenge, likely because of gaps in our understanding of the
mutagenic processes acting on regulatory DNA. There is increasing evidence that TFs bound to the genome
can interfere with normal DNA replication and repair, which could lead to increased mutation rates. However,
the precise molecular mechanisms of these interactions are poorly understood. The current project will address
this gap in our understanding of mutagenesis in TF binding sites by using new experimental techniques and
computational models to directly investigate the molecular mechanisms by which TF binding can lead to
genetic mutations. Our overarching hypothesis is that TFs bound to genomic sites containing DNA lesions can
lead to inefficient repair/correction of the lesions, and consequently to increased mutation rates. Among DNA
lesions we will focus on base mismatches, which are important precursors for a majority of cancer mutations,
and are frequently generated in the genome during DNA replication, recombination, and even repair of other
lesions. Thus, mismatches retained in cancer genomes due to being bound by TF proteins are expected to
have a large contribution to the hyper-mutation signal observed at TF binding sites. It is therefore critical to
characterize the TF-DNA binding landscape in the presence of DNA mismatches (Aim 1), and to thoroughly
investigate the mechanisms by which TF binding to mismatches can lead to genetic mutations (Aim 2). Overall,
our proposed work represents a first step toward determining whether the enrichment of cancer mutations in
TF binding sites is due, at least in part, to DNA-bound TFs that act as roadblocks for DNA mismatch correction
and repair. Longer term, a thorough understanding of the role of TFs in mutagenesis at regulatory DNA will be
instrumental for developing accurate methods to identify regulatory driver mutations in cancer.

## Key facts

- **NIH application ID:** 10092203
- **Project number:** 5R01GM135658-02
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Raluca Gordan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $336,835
- **Award type:** 5
- **Project period:** 2020-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10092203

## Citation

> US National Institutes of Health, RePORTER application 10092203, The role of transcription factor proteins in mutagenesis at regulatory sites (5R01GM135658-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10092203. Licensed CC0.

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