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CBFβ Regulates RUNX3 ADP-Ribosylation to Mediate Homologous Recombination Repair

William E Samsa1, Zhen Zhang1, Zihua Gong1

  • 1Department of Cancer Biology, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, USA.

Journal of Cellular Physiology
|December 19, 2024
PubMed

Insights

RUNX3 protein stability and DNA repair are regulated by its interaction with CBFβ and PARylation. This process is crucial for homologous recombination repair at DNA double-strand break sites.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • DNA Repair Mechanisms

Background:

  • RUNX3 is a known tumor suppressor, but its precise role in cancer and DNA damage response is not fully understood.
  • The interaction of RUNX3 with CBFβ and its post-translational modifications are critical for its function.
  • Understanding RUNX3's role in DNA damage response can reveal new therapeutic targets for cancer.

Purpose of the Study:

  • To elucidate the role of RUNX3 in DNA damage response.
  • To investigate the mechanisms regulating RUNX3 stability and function.
  • To determine how RUNX3 influences homologous recombination repair.

Main Methods:

  • Investigated RUNX3 stability through ADP-ribosylation-dependent ubiquitination and degradation assays.
  • Identified and characterized new PARylation sites on RUNX3.
  • Assessed the localization of RUNX3 to DNA double-strand break sites (DBSs).
  • Analyzed the impact of RUNX3 PARylation and CBFβ heterodimerization on homologous recombination (HR) repair.

Main Results:

  • CBFβ heterodimerization stabilizes RUNX3 by preventing its degradation.
  • New PARylation sites on RUNX3 were identified, essential for its recruitment to DBSs.
  • RUNX3 PARylation and CBFβ heterodimerization enhance homologous recombination (HR) repair.
  • RUNX3 promotes HR by recruiting CtIP and phospho-RPA2 to DBSs.

Conclusions:

  • RUNX3's stability is regulated by CBFβ-mediated protection against degradation.
  • RUNX3's function in DNA double-strand break repair is dependent on its PARylation.
  • RUNX3 plays a significant role in regulating homologous recombination repair, offering potential as a therapeutic target.
Keywords:
ADP‐ribosylationCBFβRUNX3homologous recombination repair

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