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| Status |
Public on Jan 20, 2023 |
| Title |
UV irradiation remodels the specificity landscape of transcription factors [84702_Proteins] |
| Platform organism |
synthetic construct |
| Sample organism |
Homo sapiens |
| Experiment type |
Other
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| Summary |
Somatic mutations are highly enriched at transcription factor (TF) binding sites, with the strongest trend being observed for ultraviolet light (UV)-induced mutations in melanomas. One of the main mechanisms proposed for this hyper-mutation pattern is the inefficient repair of UV lesions within TF-binding sites, caused by competition between TFs bound to these lesions and the DNA repair proteins that must recognize the lesions to initiate repair. However, TF binding to UV-irradiated DNA is poorly characterized, and it is unclear whether TFs maintain specificity for their DNA sites after UV exposure. We developed UV-Bind, a high-throughput approach to investigate the impact of UV irradiation on protein-DNA binding specificity. We applied UV-Bind to ten TFs from eight structural families, and found that UV lesions significantly altered the DNA-binding preferences of all TFs tested. The main effect was a decrease in binding specificity, but the precise effects and their magnitude differ across factors. Importantly, we found that despite the overall reduction in DNA-binding specificity in the presence of UV lesions, TFs can still compete with repair proteins for lesion recognition, in a manner consistent with their specificity for UV-irradiated DNA. In addition, for a subset of TFs we identified a surprising but reproducible effect at certain non-consensus DNA sequences, where UV irradiation leads to a high increase in the level of TF binding. These changes in DNA-binding specificity after UV irradiation, at both consensus and non-consensus sites, have important implications for the regulatory and mutagenic roles of TFs in the cell.
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| Overall design |
The UV-Bind assay was performed for 10 transcription factors and 1 repair protein (UV-DDB) for UV-irradiated arrays. This array uses a universal design that allows for the measurement of k-mers, and it was used to measure ETS1 and c-MYC binding. A detailed description is provided in the manuscript.
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| Contributor(s) |
Mielko Z, Gordan R |
| Citation missing |
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| Submission date |
Jan 17, 2023 |
| Last update date |
Jan 23, 2023 |
| Contact name |
Raluca Gordan |
| E-mail(s) |
raluca.gordan@duke.edu
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| Organization name |
Duke University
|
| Department |
Center for Genomic and Computational Biology
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| Street address |
101 Science Dr, CIEMAS 2179
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| City |
Durham |
| State/province |
NC |
| ZIP/Postal code |
27708 |
| Country |
USA |
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| Platforms (1) |
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| Samples (4)
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| This SubSeries is part of SuperSeries: |
| GSE223023 |
UV irradiation remodels the specificity landscape of transcription factors |
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| Relations |
| BioProject |
PRJNA924719 |
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