CHFR-mediated degradation of RNF126 confers sensitivity to PARP inhibitors in triple-negative breast cancer cells
CHFR-mediated degradation of RNF126 confers sensitivity to PARP inhibitors in triple-negative breast cancer cells
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CHFR 介导的 RNF126 降解赋予三阴性乳腺癌细胞对 PARP 抑制剂的敏感性。
DOI：
10.1016/j.bbrc.2021.08.011
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发表时间：
2021
影响因子：
3.1
通讯作者：
Hu Kaishun
中科院分区：
文献类型：
--
作者：
Wu Wenjing;Zhao Jianli;Xiao Jianhong;Wu Weijun;Xie Limin;Xie Xiaojuan;Yang Chaoye;Yin Dong;Hu Kaishun
环指蛋白126（Ring-finger protein 126，RNF 126）是一种E3泛素连接酶，在细胞增殖、DNA损伤修复和胞内囊泡运输等生物学过程中发挥着重要作用。RNF 126是否受翻译后修饰的调节还知之甚少。在这里，我们表明，PARP 1相互作用和聚（ADP）核糖基化RNF 126，然后招募PAR结合E3泛素连接酶CHFR，以促进泛素化和降解RNF 126。此外，RNF 126是激活由辐射（IR）或PARP抑制剂（PARPi）诱导的ATR-Chk 1信号传导所必需的，并且RNF 126的耗尽增加了三阴性乳腺癌（TNBC）细胞对PARPi治疗的敏感性。我们的发现表明PARPi介导的RNF 126蛋白稳定性的上调有助于TNBC细胞对PARPi的抗性。因此，靶向E3泛素连接酶RNF 126可能是在临床试验中克服TNBC细胞对PARPi的抗性的新治疗。
Ring-finger protein 126 (RNF126), an E3 ubiquitin ligase, plays crucial roles in various biological processes, including cell proliferation, DNA damage repair, and intracellular vesicle trafficking. Whether RNF126 is modulated by posttranslational modifications is poorly understood. Here, we show that PARP1 interacts with and poly(ADP)ribosylates RNF126, which then recruits the PAR-binding E3 ubiquitin ligase CHFR to promote ubiquitination and degradation of RNF126. Moreover, RNF126 is required for the activation of ATR-Chk1 signaling induced by either irradiation (IR) or a PARP inhibitor (PARPi), and depletion of RNF126 increases the sensitivity of triple-negative breast cancer (TNBC) cells to PARPi treatment. Our findings suggest that PARPi-mediated upregulation of RNF126 protein stability contributes to TNBC cell resistance to PARPi. Therefore, targeting the E3 ubiquitin ligase RNF126 may be a novel treatment for overcoming the resistance of TNBC cells to PARPi in clinical trials.