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UV irradiation remodels the specificity landscape of transcription factors.

Publication ,  Journal Article
Mielko, Z; Zhang, Y; Sahay, H; Liu, Y; Schaich, MA; Schnable, B; Morrison, AM; Burdinski, D; Adar, S; Pufall, M; Van Houten, B; Gordân, R; Afek, A
Published in: Proceedings of the National Academy of Sciences of the United States of America
March 2023

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 hypermutation 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 the 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 nonconsensus 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 nonconsensus sites, have important implications for the regulatory and mutagenic roles of TFs in the cell.

Duke Scholars

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Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

March 2023

Volume

120

Issue

11

Start / End Page

e2217422120

Related Subject Headings

  • Ultraviolet Rays
  • Transcription Factors
  • Protein Binding
  • Humans
  • DNA
  • Binding Sites
 

Citation

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Mielko, Z., Zhang, Y., Sahay, H., Liu, Y., Schaich, M. A., Schnable, B., … Afek, A. (2023). UV irradiation remodels the specificity landscape of transcription factors. Proceedings of the National Academy of Sciences of the United States of America, 120(11), e2217422120. https://doi.org/10.1073/pnas.2217422120
Mielko, Zachery, Yuning Zhang, Harshit Sahay, Yiling Liu, Matthew A. Schaich, Brittani Schnable, Abigail M. Morrison, et al. “UV irradiation remodels the specificity landscape of transcription factors.Proceedings of the National Academy of Sciences of the United States of America 120, no. 11 (March 2023): e2217422120. https://doi.org/10.1073/pnas.2217422120.
Mielko Z, Zhang Y, Sahay H, Liu Y, Schaich MA, Schnable B, et al. UV irradiation remodels the specificity landscape of transcription factors. Proceedings of the National Academy of Sciences of the United States of America. 2023 Mar;120(11):e2217422120.
Mielko, Zachery, et al. “UV irradiation remodels the specificity landscape of transcription factors.Proceedings of the National Academy of Sciences of the United States of America, vol. 120, no. 11, Mar. 2023, p. e2217422120. Epmc, doi:10.1073/pnas.2217422120.
Mielko Z, Zhang Y, Sahay H, Liu Y, Schaich MA, Schnable B, Morrison AM, Burdinski D, Adar S, Pufall M, Van Houten B, Gordân R, Afek A. UV irradiation remodels the specificity landscape of transcription factors. Proceedings of the National Academy of Sciences of the United States of America. 2023 Mar;120(11):e2217422120.
Journal cover image

Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

March 2023

Volume

120

Issue

11

Start / End Page

e2217422120

Related Subject Headings

  • Ultraviolet Rays
  • Transcription Factors
  • Protein Binding
  • Humans
  • DNA
  • Binding Sites