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DARPin-induced reactivation of p53 in HPV-positive cells

Philipp Münick1, Alexander Strubel1, Dimitrios-Ilias Balourdas2,3

  • 1Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Goethe University, Frankfurt, Germany.

Nature Structural & Molecular Biology
|January 9, 2025
PubMed

Insights

A novel designed protein can block human papillomavirus (HPV) oncoproteins E6 and E7, reactivating the tumor suppressor p53. This approach shows potential for preventing HPV-driven cancers by stabilizing p53 and restoring its function.

Area of Science:

  • Oncology
  • Virology
  • Molecular Biology

Background:

  • High-risk human papillomavirus (HPV) strains cause epithelial cancers worldwide.
  • HPV oncoproteins E6 and E7 drive tumorigenesis by disrupting cellular control mechanisms.
  • HPV E6 protein targets the tumor suppressor p53 for degradation via interaction with E3 ligase E6AP.

Purpose of the Study:

  • To develop a therapeutic strategy targeting the HPV E6-E6AP interaction.
  • To investigate a designed ankyrin repeat protein (DARP) as an inhibitor of HPV E6.
  • To assess the potential of DARP in reactivating p53 and preventing oncogenic transformation.

Main Methods:

  • Characterization of a DARP designed to bind the HPV E6 protein.
  • Assessing the DARP's effect on the E6-E6AP complex formation.
  • Evaluating p53 stabilization and transcriptional activity in HPV-positive cancer cell lines (HeLa and SiHa).

Main Results:

  • The DARP successfully binds to the same site as HPV E6, displacing E3 ligase E6AP.
  • This interaction leads to the stabilization of p53.
  • p53-dependent transcription was reactivated in HPV18-positive HeLa and HPV16-positive SiHa cells.
  • The DARP did not interfere with p53 DNA binding or the MDM2 negative feedback loop.

Conclusions:

  • Designed ankyrin repeat proteins can effectively inhibit HPV E6 oncoprotein activity.
  • Reactivation of p53 by DARP offers a potential therapeutic strategy against HPV-induced cancers.
  • This approach represents a promising avenue for cancer prevention and treatment.

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