UV irradiation remodels the specificity landscape of transcription factors

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Somatic mutations frequently occur at transcription factor (TF) binding sites, particularly UV-induced mutations in melanoma.
• A proposed mechanism is inefficient DNA repair at TF-bound UV lesions due to competition between TFs and repair proteins.
• The effect of UV irradiation on TF binding specificity and competition with repair proteins remains poorly understood.

Purpose of the Study:

• To investigate the impact of UV irradiation on protein-DNA binding specificity.
• To characterize TF binding to UV-irradiated DNA and their competition with DNA repair proteins.
• To understand how UV-induced DNA damage influences TF binding preferences.

Main Methods:

• Development of UV-Bind, a high-throughput method to assess UV irradiation's effect on protein-DNA binding.
• Application of UV-Bind to ten transcription factors from eight structural families.
• Analysis of changes in TF binding preferences and specificity upon UV exposure.

Main Results:

• UV lesions significantly altered DNA-binding preferences for all tested TFs, generally decreasing specificity.
• TF binding specificity changes varied in magnitude and nature across different TFs.
• TFs competed with repair proteins for UV lesion recognition, maintaining some specificity.
• Certain nonconsensus DNA sites showed increased TF binding after UV irradiation for some TFs.

Conclusions:

• UV irradiation alters TF binding specificity, impacting TF-DNA interactions and potentially mutation patterns.
• TFs can still compete with DNA repair machinery for UV lesions, influencing repair efficiency.
• Altered TF binding at both consensus and nonconsensus sites has implications for gene regulation and mutagenesis in response to UV damage.