RNF126-Mediated MRE11 Ubiquitination Activates the DNA Damage Response and Confers Resistance of Triple-Negative Breast Cancer to Radiotherapy.
RNF126-Mediated MRE11 Ubiquitination Activates the DNA Damage Response and Confers Resistance of Triple-Negative Breast Cancer to Radiotherapy.
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RNF126 介导的 MRE11 泛素化激活 DNA 损伤反应并赋予三阴性乳腺癌对放射治疗的抵抗力
DOI：
10.1002/advs.202203884
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发表时间：
2023-02
期刊：
影响因子：
15.1
通讯作者：
Chen, Ceshi
中科院分区：
文献类型：
--
作者：
Liu, Wenjing;Zheng, Min;Zhang, Rou;Jiang, Qiuyun;Du, Guangshi;Wu, Yingying;Yang, Chuanyu;Li, Fubing;Li, Wei;Wang, Luzhen;Wu, Jiao;Shi, Lei;Li, Wenhui;Zhang, Kai;Zhou, Zhongmei;Liu, Rong;Gao, Yingzheng;Huang, Xinwei;Fan, Songqing;Zhi, Xu;Jiang, Dewei;Chen, Ceshi
关键词：
三阴性乳腺癌（TNBC）具有较高的分子异质性和转移潜力，预后最差。由于针对TNBC的治疗方法有限，放射（IR）治疗仍然是淋巴结或脑转移患者的常见治疗选择。因此，迫切需要制定策略来增强TNBC肿瘤对低剂量IR的敏感性。在这里，作者报告说，E3泛素连接酶环指蛋白126（RNF 126）对于IR诱导的ATR-CHK 1通路激活以增强DNA损伤修复（DDR）非常重要。从机制上讲，RNF 126与MRE 11-RAD 50-NBS 1（MRN）复合物物理结合，并在K339和K480处泛素化MRE 11，以增加其DNA核酸外切酶活性，随后的RPA结合和ATR磷酸化，以同源重组修复倾向的方式促进持续的DDR。因此，RNF 126的耗尽导致TNBC细胞和小鼠中基因组不稳定性和辐射敏感性增加。此外，发现RNF 126表达由IR激活HER 2-AKT-NF-κB途径诱导，并且用双氢青蒿素靶向RNF 126表达显著提高了脑中TNBC肿瘤对体内IR治疗的敏感性。总之，这些结果表明，RNF 126介导的MRE 11泛素化是DDR的关键调节因子，这为提高TNBC对放疗的敏感性提供了一个有希望的靶点。RNF 126首次被报道介导MRE 11的非降解性泛素化，以促进其核酸外切酶活性并促进同源重组修复，这是由TNBC细胞中IR活化HER 2-AKT-NF-κB途径诱导的。双氢青蒿素是一种有效的抗疟药物，在TNBC小鼠脑肿瘤模型上被证明能抑制RNF 126的表达，增强放射治疗增敏作用，具有很高的临床应用潜力。
Triple‐negative breast cancer (TNBC) has higher molecular heterogeneity and metastatic potential and the poorest prognosis. Because of limited therapeutics against TNBC, irradiation (IR) therapy is still a common treatment option for patients with lymph nodes or brain metastasis. Thus, it is urgent to develop strategies to enhance the sensitivity of TNBC tumors to low‐dose IR. Here, the authors report that E3 ubiquitin ligase Ring finger protein 126 (RNF126) is important for IR‐induced ATR‐CHK1 pathway activation to enhance DNA damage repair (DDR). Mechanistically, RNF126 physically associates with the MRE11‐RAD50‐NBS1 (MRN) complex and ubiquitinates MRE11 at K339 and K480 to increase its DNA exonuclease activity, subsequent RPA binding, and ATR phosphorylation, promoting sustained DDR in a homologous recombination repair‐prone manner. Accordingly, depletion of RNF126 leads to increased genomic instability and radiation sensitivity in both TNBC cells and mice. Furthermore, it is found that RNF126 expression is induced by IR activating the HER2‐AKT‐NF‐κB pathway and targeting RNF126 expression with dihydroartemisinin significantly improves the sensitivity of TNBC tumors in the brain to IR treatment in vivo. Together, these results reveal that RNF126‐mediated MRE11 ubiquitination is a critical regulator of the DDR, which provides a promising target for improving the sensitivity of TNBC to radiotherapy. RNF126 is first reported to mediate the non‐degradative ubiquitination of MRE11 to facilitate its exonuclease activity and promote homologous recombination repair, which is induced by the IR‐activating HER2‐AKT‐NF‐κB pathway in TNBC cells. Dihydroartemisinin, a potent antimalarial agent, is proven to inhibit RNF126 expression and enhance radiotherapy sensitization on mouse model with a TNBC tumor in the brain, exhibiting high potential in clinical application.
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