USP39 regulates DNA damage response and chemo-radiation resistance by deubiquitinating and stabilizing CHK2
USP39 regulates DNA damage response and chemo-radiation resistance by deubiquitinating and stabilizing CHK2
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USP39 通过去泛素化和稳定 CHK2 来调节 DNA 损伤反应和化疗放射抗性
DOI：
10.1016/j.canlet.2019.02.015
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发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
Yuan, Jian
中科院分区：
文献类型：
--
作者：
Wu, Jinhuan;Chen, Yuping;Yuan, Jian
丝氨酸/苏氨酸激酶CHK 2（检查点激酶2）是DNA损伤反应中的关键介质和肿瘤抑制剂，其涉及促进细胞周期停滞、凋亡和DNA修复。越来越多的证据表明，这些功能主要是通过磷酸化下游因子，如p53和BRCA 1发挥作用。最近的研究表明，泛素化是CHK 2的重要调控模式。然而，去泛素化酶是否参与CHK 2的调控仍不清楚。在这里，我们报告说，去泛素化酶，USP 39，是一个新的调节CHK 2。在机制上，USP 39去泛素化并稳定CHK 2，这反过来增强CHK 2的稳定性。短发夹状RNA（Short hairpin RNA，shRNA）介导的USP 39基因敲低导致CHK 2基因表达下调，从而破坏DNA损伤诱导的G2/M期检查点，减少细胞凋亡，使肿瘤细胞对化疗药物和放射治疗产生抵抗。总的来说，我们确定USP 39是CHK 2在DNA损伤反应中的一种新型调节剂。
The serine/threonine kinase, CHK2 (checkpoint kinase 2), is a key mediator in DNA damage response and a tumor suppressor, which is implicated in promoting cell cycle arrest, apoptosis and DNA repair. Accumulating evidence suggests that these functions are primarily exerted through phosphorylation downstream factors such as p53 and BRCA1. Recent studies have shown that ubiquitination is an important mode of regulation of CHK2. However, it remains largely unclear whether deubiquitinases participate in regulation of CHK2. Here, we report that a deubiquitinase, USP39, is a new regulator of CHK2. Mechanistically, USP39 deubiquitinates and stabilizes CHK2, which in turn enhances CHK2 stability. Short hairpin RNA (shRNA) mediated knockdown of USP39 led to deregulate CHK2, which resulted in compromising the DNA damage-induced G2/M checkpoint, decreasing apoptosis, and conferring cancer cells resistance to chemotherapy drugs and radiation treatment. Collectively, we identify USP39 as a novel regulator of CHK2 in the DNA damage response.