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DTX3L-mediated TIRR nuclear export and degradation regulates DNA repair pathway choice and PARP inhibitor sensitivity

Qi Ye1, Jian Ma2, Zixi Wang1

  • 1Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.

Nature Communications
|December 5, 2024
PubMed

Insights

DNA damage triggers Tudor interacting repair regulator (TIRR) degradation, impacting 53BP1 activity. DTX3L overexpression in prostate cancer disrupts this, impairing DNA repair and increasing PARP inhibitor sensitivity.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • DNA Repair Mechanisms

Background:

  • 53BP1 is crucial for DNA double-strand break (DSB) repair, with its activity modulated by Tudor interacting repair regulator (TIRR).
  • Regulation of the TIRR-53BP1 axis in response to DNA damage is not well understood.

Purpose of the Study:

  • To elucidate the regulatory mechanisms of the TIRR-53BP1 DNA repair axis upon DNA damage.
  • To investigate the role of DTX3L in regulating TIRR stability and its impact on DNA repair and PARP inhibitor sensitivity.

Main Methods:

  • Investigated TIRR localization and degradation following DNA damage.
  • Utilized ubiquitination assays to identify lysine residues and E3 ligases involved in TIRR regulation.
  • Examined the effect of DTX3L on the TIRR-53BP1 axis, DNA repair, and sensitivity to PARP inhibitors in prostate cancer models.

Main Results:

  • DNA damage induces cytoplasmic translocation and degradation of TIRR.
  • DTX3L-mediated ubiquitination at lysine 187 promotes XPO1-dependent nuclear export and degradation of TIRR.
  • DTX3L overexpression in prostate cancer leads to decreased TIRR, impaired 53BP1 regulation, HR deficiency, chromosomal instability, and enhanced PARP inhibitor sensitivity.

Conclusions:

  • DTX3L acts as an upstream regulator of the TIRR-53BP1 axis, controlling DNA repair pathway choice and PARP inhibitor sensitivity.
  • TIRR ubiquitination and DTX3L overexpression are potential biomarkers for predicting PARP inhibitor response in cancers.

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