2. Academic Validation
  3. The deubiquitination-PARylation positive feedback loop of the USP10-PARP1 axis promotes DNA damage repair and affects therapeutic efficacy of PARP1 inhibitor

The deubiquitination-PARylation positive feedback loop of the USP10-PARP1 axis promotes DNA damage repair and affects therapeutic efficacy of PARP1 inhibitor

  • Oncogene. 2025 Aug;44(29):2515-2529. doi: 10.1038/s41388-025-03428-7.
Jingwei Liu # 1 2 3,  Siyi Zhang # 1 2,  Liangzi Cao # 1 2,  Naijin Zhang # 1 4 5,  Qiqiang Guo 1 2,  Yu Zou 1 2,  Ruohan Yang 1 2,  Shiyuan Dong 1 2,  Lixia Zheng 1 2,  Yutong Xiao 1 2,  Yubang Wang 1 2,  Songming Lu 1 2,  Pengcheng Jiang 1 2,  Keshen Zhou 1 2,  Shu Chen 1 2,  Di Chen 1 2,  Hao Li 1 2,  Ying Zhang 1 4,  Ren Sheng 6,  Chengzhong Xing 7,  Xiaoyu Song 8 9,  Zhenning Wang 10,  Liu Cao 11 12
Affiliations

Affiliations

  • 1 The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning, China.
  • 2 Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning, China.
  • 3 Department of Anus and Intestine Surgery, First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China.
  • 4 Department of Cardiology, First Hospital of China Medical University, Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, Shenyang, Liaoning, China.
  • 5 NHC Key Laboratory of Advanced Reproductive Medicine and Fertility (China Medical University), National Health Commission, Shenyang, China.
  • 6 College of Life and Health Science, Northeastern University, Shenyang, Liaoning, China.
  • 7 Department of Anus and Intestine Surgery, First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China. [email protected].
  • 8 The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning, China. [email protected].
  • 9 Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning, China. [email protected].
  • 10 Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning, China. [email protected].
  • 11 The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning, China. [email protected].
  • 12 Key Laboratory of Cell Biology of Ministry of Public Health, Key Laboratory of Medical Cell Biology of Ministry of Education, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, Liaoning Province Collaborative Innovation Center of Aging Related Disease Diagnosis and Treatment and Prevention, China Medical University, Shenyang, Liaoning, China. [email protected].
  • # Contributed equally.
PMID: 40316740 DOI: 10.1038/s41388-025-03428-7
Abstract

PARP1 initiates DNA repair pathways including single-strand break repair (SSBR) by recruiting multiple DNA repair factors via poly ADP-ribosylation (PARylation) of target proteins. However, how PARP1 is stabilized and activated to promote DNA damage repair remains unclear. Here we report that DNA damage generates a ROS signal, which triggers USP10 to interact with and stabilize PARP1 by deubiquitinating the K418 site in an ATM-dependent manner. In turn, PARP1 mediates PARylation of USP10 at amino acid residues D634, D645, and E648, which further promotes the deubiquitination activity of USP10 and DNA damage response to form a positive feedback loop. PARP1 is highly expressed in breast Cancer tissues and positively correlates with USP10 protein levels. Moreover, breast Cancer cells treated with a USP10 inhibitor show increased sensitivity to PARP1 Inhibitor both in vivo and in vitro. Overall, our results unravel that the deubiquitination-PARylation positive feedback loop of the USP10-PARP1 axis promotes DNA damage repair, which might contribute to the improvement of PARP1 Inhibitor efficacy in breast Cancer treatment.

Figures
Products