# UV damage stimulation by ETS transcription factors in skin cancer

> **NIH NIH R21** · WASHINGTON STATE UNIVERSITY · 2020 · $191,850

## Abstract

PROJECT SUMMARY
 Exposure to ultraviolet (UV) light is the principal etiological agent for melanoma and other skin cancers. UV
light induces damage to the cellular DNA, primarily cyclobutane pyrimidine dimers (CPDs) and 6-4
photoproducts (6-4PPs). Sequencing of DNA from human skin cancers have revealed high levels of UV-
induced mutations that are heterogeneously distributed across the genome. It has recently been discovered
that UV-induced mutations are particularly enriched at the DNA binding sites of transcription factors. While this
has been attributed to less efficient repair at such binding sites, it is also possible that variations in initial
damage formation due to transcription factor binding could stimulate mutation rates. To test this hypothesis, we
have used our newly developed CPD-seq method to map CPD formation across the human genome
immediately following UV irradiation. Our preliminary data indicate that initial UV damage formation is
significantly elevated at many transcription factor binding sites (TFBS), particularly binding sites for the E26
transformation-specific (ETS) family of transcription factors (TFs). Importantly, stimulation of CPD formation by
ETS binding correlates with significantly higher mutation rates in melanoma tumors, indicating that variations in
initial DNA damage formation are an important contributor to the mutational 'landscape' in human cancers.
 The overall objective of this proposal is to elucidate the mechanism by which ETS binding stimulates UV
damage formation and determine whether ETS-induced CPD 'hotspots' drive recurrent mutagenesis at
individual binding sites in melanoma tumors. To investigate the mechanism by which ETS protein binding
stimulates UV damage formation, we will characterize the effects of selected ETS transcription factors on UV
damage formation and repair in vitro (Aim I). In parallel, we will use molecular dynamics simulations to model
how DNA binding by different ETS transcription factors predisposes dipyrimidine sequences to form UV
photoproducts. Finally, we will examine whether ETS TF binding inhibits repair of CPD lesions in vitro. In Aim
II, we will develop the CPD-capture-seq method to map the formation and repair of CPD lesions with high
sequencing depth and single nucleotide resolution at specific genomic regions of interest, including sites of
recurrent promoter mutations in melanoma and ETS binding sites. In parallel, we will map ETS binding sites in
human melanocytes using the ChIP-exo method. Comparison of CPD-capture-seq data with UV-induced
mutations identified in human melanomas will allow us determine with high resolution whether ETS-induced
CPD 'hotspots' and repair inhibition are associated with recurrent mutations in skin cancer. These data should
provide new insights into the etiology of some of the most recurrent mutations in melanoma, which occur at
ETS binding sites. ETS transcription factors are known oncogenes that regulate many genes involved in cell
d...

## Key facts

- **NIH application ID:** 9904652
- **Project number:** 5R21ES029655-02
- **Recipient organization:** WASHINGTON STATE UNIVERSITY
- **Principal Investigator:** John J Wyrick
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $191,850
- **Award type:** 5
- **Project period:** 2019-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9904652

## Citation

> US National Institutes of Health, RePORTER application 9904652, UV damage stimulation by ETS transcription factors in skin cancer (5R21ES029655-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9904652. Licensed CC0.

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