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Updated: May 21, 2025

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TAOK1 promotes filament formation in HR repair through phosphorylating USP7

Tian-Chen Zhu1,2, Zhang-Ping He3, Shu-Ting Li1,2

  • 1State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou 510000, China.

Proceedings of the National Academy of Sciences of the United States of America
|March 19, 2025
PubMed

Insights

Thousand and one amino acid protein kinase 1 (TAOK1) inhibition enhances PARP inhibitor efficacy in cancer. Blocking TAOK1 or its interaction with USP7 degrades RAD51, disrupting DNA repair and increasing cancer cell sensitivity to PARP inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Poly-ADP-ribose polymerase (PARP) inhibitors are key cancer therapies for tumors with homologous recombination (HR) defects.
  • Expanding the clinical use of PARP inhibitors is limited by resistance mechanisms.

Purpose of the Study:

  • To identify novel targets for synthetic lethality with PARP inhibitors.
  • To investigate the role of thousand and one amino acid protein kinase 1 (TAOK1) in DNA damage response and PARP inhibitor resistance.

Main Methods:

  • High-throughput kinase inhibitor screening to find targets synthetically lethal with PARP inhibitors.
  • Genetic depletion and pharmacological inhibition of TAOK1.
  • Assessment of RAD51 stability and HR repair function.
  • Evaluation of cancer cell sensitivity to PARP inhibition.

Main Results:

  • TAOK1 phosphorylates ubiquitin specific peptidase 7 (USP7), enhancing its activity.
  • USP7 activity prevents RAD51 ubiquitylation and degradation, preserving HR repair.
  • Inhibiting TAOK1 or USP7 function leads to RAD51 degradation and HR repair defects.
  • TAOK1 inhibition or USP7 blocking peptides increase cancer cell sensitivity to PARP inhibitors.

Conclusions:

  • TAOK1 is a critical regulator of the HR repair pathway in human cancer cells.
  • Combining PARP inhibitors with TAOK1 inhibition or USP7-targeting peptides offers a strategy to overcome PARPi resistance.
  • This approach holds potential for improving therapeutic outcomes in cancer treatment.
Keywords:
PARP inhibitorTAOK1bladder cancerhomologous recombinationsynthetic lethality

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