A20/TNFAIP3 Regulates the DNA Damage Response and Mediates Tumor Cell Resistance to DNA-Damaging Therapy
A20/TNFAIP3 Regulates the DNA Damage Response and Mediates Tumor Cell Resistance to DNA-Damaging Therapy
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A20/TNFAIP3 调节 DNA 损伤反应并介导肿瘤细胞对 DNA 损伤治疗的抵抗
DOI：
10.1158/0008-5472.can-17-2143
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发表时间：
2018
期刊：
影响因子：
11.2
通讯作者：
Zheng Xiaofeng
中科院分区：
文献类型：
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作者：
Yang Chuanzhen;Zang Weicheng;Tang Zefang;Ji Yapeng;Xu Ruidan;Yang Yongfeng;Luo Aiping;Hu Bin;Zhang Zemin;Liu Zhihua;Zheng Xiaofeng
一个合格的DNA损伤反应（DDR）有助于预防癌症，但一旦癌症出现，DDR可以削弱化疗和放疗的疗效，导致癌细胞中致命的DNA断裂。因此，阻断DDR可以提高这些模式的功效。在这里，我们报告了一种新的DDR机制，它与炎症信号相互作用，并可能被阻断以改善抗癌结果。具体来说，我们报告说，泛素编辑酶A20/TNFAIP 3结合并抑制E3泛素连接酶RNF 168，这是负责调节组蛋白H2 A营业额的关键适当的DNA修复。DNA损伤后诱导的A20以独立于其酶活性的方式破坏RNF 168-H2 A相互作用。此外，它还抑制了DNA修复过程中RNF 168和下游修复蛋白53 BP 1的积累。修复后，从损伤部位拆卸RNF 168和53 BP 1也需要A20。相反，A20缺失增加了易错非同源DNA末端连接的效率，减少了无错DNA同源重组，使基因组不稳定，并增加了对DNA损伤的敏感性。在浸润性乳腺癌的临床标本中，A20广泛过表达，与其作为治疗靶点的候选资格一致。综上所述，我们的发现表明A20对于癌细胞中DDR的正常功能至关重要，并且它建立了这种NFκ B调节的泛素编辑酶和DDR pathway.Significance之间的新联系：本研究将泛素编辑酶A20鉴定为介导癌细胞对DNA损伤疗法的抗性的关键因素，并暗示阻断其功能以利用化疗和放疗的功效。Cancer Res; 78（4）; 1069-82。©2017 AACR.
A competent DNA damage response (DDR) helps prevent cancer, but once cancer has arisen, DDR can blunt the efficacy of chemotherapy and radiotherapy that cause lethal DNA breakage in cancer cells. Thus, blocking DDR may improve the efficacy of these modalities. Here, we report a new DDR mechanism that interfaces with inflammatory signaling and might be blocked to improve anticancer outcomes. Specifically, we report that the ubiquitin-editing enzyme A20/TNFAIP3 binds and inhibits the E3 ubiquitin ligase RNF168, which is responsible for regulating histone H2A turnover critical for proper DNA repair. A20 induced after DNA damage disrupted RNF168–H2A interaction in a manner independent of its enzymatic activity. Furthermore, it inhibited accumulation of RNF168 and downstream repair protein 53BP1 during DNA repair. A20 was also required for disassembly of RNF168 and 53BP1 from damage sites after repair. Conversely, A20 deletion increased the efficiency of error-prone nonhomologous DNA end-joining and decreased error-free DNA homologous recombination, destablizing the genome and increasing sensitivity to DNA damage. In clinical specimens of invasive breast carcinoma, A20 was widely overexpressed, consistent with its candidacy as a therapeutic target. Taken together, our findings suggest that A20 is critical for proper functioning of the DDR in cancer cells and it establishes a new link between this NFκB-regulated ubiquitin-editing enzyme and the DDR pathway.Significance:This study identifies the ubiquitin-editing enzyme A20 as a key factor in mediating cancer cell resistance to DNA-damaging therapy, with implications for blocking its function to leverage the efficacy of chemotherapy and radiotherapy.Cancer Res; 78(4); 1069–82. ©2017 AACR.