Pharmacological inhibition of BAP1 recruits HERC2 to competitively dissociate BRCA1-BARD1, suppresses DNA repair and sensitizes CRC to radiotherapy.

Xin Yue; Tingyu Liu; Xuecen Wang; Weijian WU; Gesi Wen; Yang YI; Jiaxin WU; Ziyang Wang; Weixiang Zhan; Ruirui WU; Yuan Meng; Zhirui Cao; Liyuan LE; Wenyan Qiu; Xiaoyue Zhang; Zhenyu LI; Yong Chen; Guohui Wan; Xianzhang BU; Zhenwei Peng; Ran-yi Liu

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Pharmacological inhibition of BAP1 recruits HERC2 to competitively dissociate BRCA1-BARD1, suppresses DNA repair and sensitizes CRC to radiotherapy.

Author: Xin YUE ¹ ; Tingyu LIU ¹ ; Xuecen WANG ² ; Weijian WU ³ ; Gesi WEN ⁴ ; Yang YI ² ; Jiaxin WU ³ ; Ziyang WANG ⁵ ; Weixiang ZHAN ⁶ ; Ruirui WU ³ ; Yuan MENG ¹ ; Zhirui CAO ⁷ ; Liyuan LE ⁸ ; Wenyan QIU ⁸ ; Xiaoyue ZHANG ² ; Zhenyu LI ¹ ; Yong CHEN ² ; Guohui WAN ³ ; Xianzhang BU ³ ; Zhenwei PENG ² ; Ran-Yi LIU ¹
Author Information

1. State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
2. Department of Radiation Oncology, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
3. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
4. Department of Clinical Research, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.
5. Department of Gastrointestinal Surgery, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
6. Department of Oncology, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China.
7. Department of Traditional Chinese Medicine, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
8. Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
Publication Type:Journal Article
Keywords: BAP1; BARD1; BRCA1; CRC radiosensitization; Competitively dissociation; HERC2 recruitment; HR-Mediated DNA repair; Pharmacological inhibition
From: Acta Pharmaceutica Sinica B 2023;13(8):3382-3399
CountryChina
Language:English
Abstract: Radiotherapy is widely used in the management of advanced colorectal cancer (CRC). However, the clinical efficacy is limited by the safe irradiated dose. Sensitizing tumor cells to radiotherapy via interrupting DNA repair is a promising approach to conquering the limitation. The BRCA1-BARD1 complex has been demonstrated to play a critical role in homologous recombination (HR) DSB repair, and its functions may be affected by HERC2 or BAP1. Accumulated evidence illustrates that the ubiquitination-deubiquitination balance is involved in these processes; however, the precise mechanism for the cross-talk among these proteins in HR repair following radiation hasn't been defined. Through activity-based profiling, we identified PT33 as an active entity for HR repair suppression. Subsequently, we revealed that BAP1 serves as a novel molecular target of PT33 via a CRISPR-based deubiquitinase screen. Mechanistically, pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction, interrupting HR repair. Consequently, PT33 treatment can substantially enhance the sensitivity of CRC cells to radiotherapy in vitro and in vivo. Overall, these findings provide a mechanistic basis for PT33-induced HR suppression and may guide an effective strategy to improve therapeutic gain.