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 |
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Erscheinungsjahr: |
2018 |
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Erschienen: |
2018 |
Enthalten in: |
Zur Gesamtaufnahme - volume:293 |
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Enthalten in: |
The Journal of biological chemistry - 293(2018), 48 vom: 30. Nov., Seite 18624-18635 |
Sprache: |
Englisch |
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Beteiligte Personen: |
Madison, Bethany J [VerfasserIn] |
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Links: |
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Anmerkungen: |
Date Completed 29.04.2019 Date Revised 05.02.2021 published: Print-Electronic PDB: 4IRI, 1FOS, 3JTG Citation Status MEDLINE |
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doi: |
10.1074/jbc.RA118.003352 |
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funding: |
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Förderinstitution / Projekttitel: |
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PPN (Katalog-ID): |
NLM289499968 |
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100 | 1 | |a Madison, Bethany J |e verfasserin |4 aut | |
245 | 1 | 0 | |a Electrostatic repulsion causes anticooperative DNA binding between tumor suppressor ETS transcription factors and JUN-FOS at composite DNA sites |
264 | 1 | |c 2018 | |
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500 | |a Date Revised 05.02.2021 | ||
500 | |a published: Print-Electronic | ||
500 | |a PDB: 4IRI, 1FOS, 3JTG | ||
500 | |a Citation Status MEDLINE | ||
520 | |a © 2018 Madison et al. | ||
520 | |a 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 | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Research Support, N.I.H., Extramural | |
650 | 4 | |a Research Support, Non-U.S. Gov't | |
650 | 4 | |a AP1 transcription factor (AP1) | |
650 | 4 | |a ETS transcription factor family | |
650 | 4 | |a JUN–FOS complex | |
650 | 4 | |a gene expression | |
650 | 4 | |a prostate cancer | |
650 | 4 | |a protein–DNA interaction | |
650 | 4 | |a protein–protein interaction | |
650 | 4 | |a transcriptional regulation | |
650 | 4 | |a tumor suppressor gene | |
650 | 7 | |a EHF protein, human |2 NLM | |
650 | 7 | |a ERG protein, human |2 NLM | |
650 | 7 | |a Proto-Oncogene Proteins c-ets |2 NLM | |
650 | 7 | |a Proto-Oncogene Proteins c-fos |2 NLM | |
650 | 7 | |a Proto-Oncogene Proteins c-jun |2 NLM | |
650 | 7 | |a Transcription Factors |2 NLM | |
650 | 7 | |a Transcriptional Regulator ERG |2 NLM | |
650 | 7 | |a DNA |2 NLM | |
650 | 7 | |a 9007-49-2 |2 NLM | |
700 | 1 | |a Clark, Kathleen A |e verfasserin |4 aut | |
700 | 1 | |a Bhachech, Niraja |e verfasserin |4 aut | |
700 | 1 | |a Hollenhorst, Peter C |e verfasserin |4 aut | |
700 | 1 | |a Graves, Barbara J |e verfasserin |4 aut | |
700 | 1 | |a Currie, Simon L |e verfasserin |4 aut | |
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