Electrostatic repulsion causes anticooperative DNA binding between tumor suppressor ETS transcription factors and JUN–FOS at composite DNA sites

Bethany J. Madison, Kathleen A. Clark, Niraja Bhachech, Peter C. Hollenhorst, Barbara J. Graves, Simon L. Currie

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Many different transcription factors (TFs) regulate gene expression in a combinatorial fashion, often by binding in close proximity to each other on composite cis-regulatory DNA elements. Here, we investigated how ETS TFs bind with the AP1 TFs JUN–FOS at composite DNA-binding sites. DNA-binding ability with JUN–FOS correlated with the phenotype of ETS proteins in prostate cancer. We found that the oncogenic ETS-related gene (ERG) and ETS variant (ETV) 1/4/5 subfamilies co-occupy ETS–AP1 sites with JUN–FOS in vitro, whereas JUN–FOS robustly inhibited DNA binding by the tumor suppressors ETS homologous factor (EHF) and SAM pointed domain– containing ETS TF (SPDEF). EHF bound ETS–AP1 DNA with tighter affinity than ERG in the absence of JUN–FOS, possibly enabling EHF to compete with ERG and JUN–FOS for binding to ETS–AP1 sites. Genome-wide mapping of EHF- and ERG-binding sites in prostate epithelial cells revealed that EHF is preferentially excluded from closely spaced ETS–AP1 DNA sequences. Structural modeling and mutational analyses indicated that adjacent positively charged surfaces from EHF and JUN–FOS use electrostatic repulsion to disfavor simultaneous DNA binding. Conservation of positive residues on the JUN–FOS interface identified E74-like ETS TF 1 (ELF1) as an additional ETS TF exhibiting anticooperative DNA binding with JUN–FOS, and we found that ELF1 is frequently down-regulated in prostate cancer. In summary, divergent electrostatic features of ETS TFs at their JUN–FOS interface enable distinct binding events at ETS–AP1 DNA sites, which may drive specific targeting of ETS TFs to facilitate distinct transcriptional programs.

Original languageEnglish (US)
Pages (from-to)18624-18635
Number of pages12
JournalJournal of Biological Chemistry
Volume293
Issue number48
DOIs
StatePublished - Nov 30 2018

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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