TAOK1 promotes filament formation in HR repair through phosphorylating USP7

• 成果类型: Article
• 署名作者: Zhu, Tian-Chen; He, Zhang-Ping; Li, Shu-Ting; Zheng, Lin; Zheng, Xue-Yi; Lan, Xia-Lu; Qu, Chun-Hua; Nie, Run-Cong; Gu, Chao; Huang, Li-Ning; Cai, Xiao-Xia; Xiang, Zhi-Cheng; Xie, Dan; Cai, Mu-Yan
• 署名单位: State Key Lab Oncology South China; Sun Yat Sen University; State Key Lab Oncology South China; Sun Yat Sen University; Guangzhou Medical University; Fujian Medical University; Fujian Medical University; Sun Yat Sen University; State Key Lab Oncology South China; Nanjing Medical University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12937
• DOI: 10.1073/pnas.2422262122
• 发表日期: 2025-03-25
• 关键词: metastatic urothelial carcinoma; hippo pathway; STABILITY; therapy; kinase; cancer; multicenter; inhibition; PROTECTION; protein

摘要

Poly-ADP-ribose polymerase (PARP) inhibitors are vital therapeutic agents that exploit synthetic lethality, particularly effective in tumors with homologous recombination (HR) defects. However, broadening their clinical utility remains a significant challenge. In this study, we conducted a high-throughput kinase inhibitor screen to identify potential targets exhibiting synthetical lethality with PARP inhibitors. Our results show that thousand and one amino acid protein kinase 1 (TAOK1) plays a pivotal role in the DNA damage response by phosphorylating ubiquitin specific peptidase 7 (USP7), thereby promoting its enzymatic activity and preventing the ubiquitylation and subsequent degradation of RAD51, a crucial protein in the filament formation of HR repair. Notably, genetic depletion or pharmacological inhibition of TAOK1, as well as blocking peptide targeting the USP7 phosphorylation site, impaired USP7 function, leading to RAD51 degradation, disruption of HR repair, and increased tumor cell and sensitivity to PARP inhibition. This study highlights TAOK1 as a critical regulator of HR repair pathway in human cancer cells and presents a therapeutic strategy overcoming resistance to PARPi inhibitors. These findings support the potential clinical application of combining PARP inhibitors with TAOK1 inhibition or peptide treatment to improve therapeutic outcomes.