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DNA binding alters ARv7 dimer interactions

Fatma Özgün1, Zeynep Kaya1, Tunç Morova2

  • 1School of Medicine, Koç University, Istanbul 34450, Turkey.

Journal of Cell Science
|July 28, 2021
PubMed

Insights

Androgen receptor splice variant 7 (ARv7) forms heterodimers with full-length AR (ARfl) in the nucleus. These complexes interact dynamically with DNA, influencing castration-resistant prostate cancer progression.

Area of Science:

  • Molecular Biology
  • Biophysics
  • Cancer Research

Background:

  • Androgen receptor (AR) splice variants, particularly AR splice variant 7 (ARv7), are implicated in lethal castration-resistant prostate cancer.
  • ARv7 expression correlates with resistance to advanced anti-androgen therapies.
  • The interaction between ARv7 and full-length AR (ARfl) is not well understood.

Purpose of the Study:

  • To investigate the biophysical properties of ARfl/ARv7 heterodimers.
  • To elucidate the dynamics of ARv7 and ARfl interactions in the nucleus.
  • To understand how these interactions affect DNA binding and transcriptional activity.

Main Methods:

  • Fluorescence resonance energy transfer (FRET) to study protein proximity and interactions.
  • Fluorescence recovery after photobleaching (FRAP) to assess protein dynamics.
  • Nuclear localization and DNA binding studies of AR variants.

Main Results:

  • ARfl and ARv7 form stable heterodimers in the nucleus through N/C-terminal interactions.
  • ARfl/ARv7 heterodimers exhibit conformational changes upon DNA binding.
  • ARv7 homodimers and ARfl/ARv7 heterodimers show transient DNA binding at accessible ARfl sites.
  • DNA binding dynamics are determined by individual AR monomers, not dimer composition.

Conclusions:

  • ARfl/ARv7 heterodimerization is a key feature of nuclear AR signaling in prostate cancer.
  • ARv7's transcriptional activity is modulated by its interaction with ARfl and DNA binding dynamics.
  • These findings provide insights into the mechanisms driving castration-resistant prostate cancer.
Keywords:
ARv7Androgen receptorConfocal microscopyFluorescence recovery after photobleachingFluorescence resonance energy transferProstate cancer

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