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

© 2018 Madison et al..

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.

Medienart:

E-Artikel

Erscheinungsjahr:

2018

Erschienen:

2018

Enthalten in:

Zur Gesamtaufnahme - volume:293

Enthalten in:

The Journal of biological chemistry - 293(2018), 48 vom: 30. Nov., Seite 18624-18635

Sprache:

Englisch

Beteiligte Personen:

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

Links:

Volltext

Themen:

9007-49-2
AP1 transcription factor (AP1)
DNA
EHF protein, human
ERG protein, human
ETS transcription factor family
Gene expression
JUN–FOS complex
Journal Article
Prostate cancer
Protein–DNA interaction
Protein–protein interaction
Proto-Oncogene Proteins c-ets
Proto-Oncogene Proteins c-fos
Proto-Oncogene Proteins c-jun
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Transcription Factors
Transcriptional Regulator ERG
Transcriptional regulation
Tumor suppressor gene

Anmerkungen:

Date Completed 29.04.2019

Date Revised 05.02.2021

published: Print-Electronic

PDB: 4IRI, 1FOS, 3JTG

Citation Status MEDLINE

doi:

10.1074/jbc.RA118.003352

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM289499968