Pharmacological inhibition of BAP1 recruits HERC2 to competitively dissociate BRCA1-BARD1, suppresses DNA repair and sensitizes CRC to radiotherapy.
Pharmacological inhibition of BAP1 recruits HERC2 to competitively dissociate BRCA1-BARD1, suppresses DNA repair and sensitizes CRC to radiotherapy.
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BAP1的药理抑制作用募集HERC2以竞争性分离BRCA1-BARD1，抑制DNA修复并使CRC对放射疗法敏感。
DOI：
10.1016/j.apsb.2023.05.017
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发表时间：
2023-08
期刊：
影响因子：
--
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中科院分区：
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放射治疗被广泛应用于晚期结直肠癌(CRC)的治疗。然而，临床疗效受到安全照射剂量的限制。通过阻断DNA修复使肿瘤细胞对放射治疗增敏是克服这一局限性的一种很有前途的方法。已证实BRCA1-BARD1复合体在同源重组(HR)DSB修复中起关键作用，其功能可能受HERC2或BAP1的影响。越来越多的证据表明，泛素化-去泛素化平衡参与了这些过程；然而，这些蛋白质之间在辐射后HR修复中串扰的确切机制尚未确定。通过基于活动的分析，我们确定PT33是HR修复抑制的活性实体。随后，我们通过基于CRISPR的脱泛素酶筛选，揭示了BAP1作为PT33的一个新的分子靶点。从机制上讲，药物共价抑制BAP1与PT33新兵HERC2竞争BRCA1相互作用，中断HR修复。因此，PT33处理可显著提高结直肠癌细胞在体内外对放射治疗的敏感性。总体而言，这些发现为PT33诱导的心率抑制提供了一个机制基础，并可能指导一种有效的策略来提高治疗收益。药物共价抑制BAP1与PT33新兵HERC2竞争BRCA1相互作用，导致BRCA1介导的HR修复中断。
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. Pharmacological covalent inhibition of BAP1 with PT33 recruits HERC2 to compete with BARD1 for BRCA1 interaction, resulting in the interruption of BRCA1-mediated HR repair.
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影响因子：
3.5
作者：
Atanassov BS;Koutelou E;Dent SY
通讯作者：
Dent SY
USP22与PALB2相互作用，并通过DNA双链断裂的同源重组来促进化学疗法抗性。
DOI：
10.1158/1541-7786.mcr-19-0053
发表时间：
2020-03
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
通讯作者：
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影响因子：
14.8
作者：
Liang, Qin;Dexheimer, Thomas S.;Zhang, Ping;Rosenthal, Andrew S.;Villamil, Mark A.;You, Changjun;Zhang, Qiuting;Chen, Junjun;Ott, Christine A.;Sun, Hongmao;Luci, Diane K.;Yuan, Bifeng;Simeonov, Anton;Jadhav, Ajit;Xiao, Hui;Wang, Yinsheng;Maloney, David J.;Zhuang, Zhihao
通讯作者：
Zhuang, Zhihao
影响因子：
64.8
作者：
通讯作者：
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DOI：
10.1016/j.ijrobp.2015.05.037
发表时间：
2015-10-01
期刊：
International journal of radiation oncology, biology, physics
影响因子：
--
作者：
Kan C;Zhang J
通讯作者：
Zhang J