TAOK1 promotes filament formation in HR repair through phosphorylating USP7
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (14)
Tian-Chen Zhu
State 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
Zhang-Ping He
Institute of Basic Medical Sciences, School of Basic Medical Sciences, Guangzhou Medical University
Shu-Ting Li
State 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
Lin Zheng
Department of Pathology and Institute of Oncology, The School of Basic Medical Sciences, Fujian Medical University
Xue-Yi Zheng
Department of Pathology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Xia-Lu Lan
Department of Pathology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Chun-Hua Qu
Department of Pathology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Run-Cong Nie
Department of Gastric Surgery, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Chao Gu
Department of General Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University
Li-Ning Huang
Department of General Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University
Xiao-Xia Cai
State 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
Zhi-Cheng Xiang
Department of Pathology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine
Dan Xie
Mu-Yan Cai
State 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