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High Sensitivity Measurement of Transcription Factor-DNA Binding Affinities by Competitive Titration Using Fluorescence Microscopy
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An interaction proteomics survey of transcription factor binding at recurrent TERT promoter mutations

Matthew M Makowski1, Esther Willems1, Jun Fang2

  • 1Radboud Institute of Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.

Proteomics
|November 11, 2015
PubMed

Insights

Cancer-driving mutations in the TERT promoter create new binding sites for transcription factors. These factors, ELF1 and GABP, compete for binding, influencing gene activity and cancer development.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Aberrant telomerase reactivation is crucial for cancer development.
  • Recurrent mutations in the TERT promoter are common in many cancers.
  • These mutations create novel E26 transformation-specific (ETS) motifs, increasing TERT expression.

Purpose of the Study:

  • To investigate transcription factor binding at TERT promoter mutations.
  • To understand the role of ELF1 and GABP in TERT promoter regulation.
  • To characterize the competitive binding dynamics between ELF1 and GABP.

Main Methods:

  • Unbiased proteome-wide survey of transcription factor binding.
  • In vitro binding assays for ELF1 and GABP.
  • Analysis of spatial architecture of ETS motifs in the TERT promoter.
  • Characterization of competitive binding dynamics.

Main Results:

  • ELF1 binds to both TERT promoter mutations in vitro.
  • Increased GABP recruitment is facilitated by the spatial architecture of ETS motifs.
  • Transcriptionally active GABP excludes ELF1 binding.
  • Mutation-specific transcription factor binding at oncogenic TERT promoter mutations.

Conclusions:

  • TERT promoter mutations alter transcription factor binding profiles.
  • Competitive binding between ELF1 and GABP influences TERT expression.
  • This study provides insights into the molecular mechanisms of oncogenic TERT promoter mutations.
Keywords:
BiomedicineMelanomaTelomeraseTranscription

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