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Nudix Hydrolase NUDT16 Regulates 53BP1 Protein by Reversing 53BP1 ADP-Ribosylation.
Cancer Research ( IF 12.5 ) Pub Date : 2020-01-07 , DOI: 10.1158/0008-5472.can-19-2205
Fan Zhang 1 , Lihong Lou 1 , Bo Peng 1 , Xiaotian Song 1 , Ofer Reizes 2 , Alexandru Almasan 1 , Zihua Gong 1
Affiliation  

53BP1 controls two downstream subpathways, one mediated by PTIP and Artemis and the other by RIF1 and MAD2L2/Shieldin, to coordinate DNA repair pathway choices. However, the upstream regulator(s) of 53BP1 function in DNA repair remain unknown. We and others recently reported that TIRR associates with 53BP1 to stabilize it and prevents 53BP1 localization to DNA damage sites by blocking 53BP1 Tudor domain binding to H4K20me2 sites. Here, we report that the Nudix hydrolase NUDT16, a TIRR homolog, regulates 53BP1 stability. We identified a novel posttranslational modification of 53BP1 by ADP-ribosylation that is targeted by a PAR-binding E3 ubiquitin ligase, RNF146, leading to 53BP1 polyubiquitination and degradation. In response to DNA damage, ADP-ribosylated 53BP1 increased significantly, resulting in its ubiquitination and degradation. These data suggest that NUDT16 plays a major role in controlling 53BP1 levels under both normal growth conditions and during DNA damage. Notably, overexpression of a NUDT16 catalytically inactive mutant blocked 53BP1 localization to double-strand breaks because (i) the mutant binding to TIRR increased after IR; (ii) the mutant enhanced 53BP1 Tudor domain binding to TIRR, and (iii) the mutant impaired the interaction of 53BP1 Tudor domain with H4K20me2. Moreover, NUDT16's catalytic hydrolase activity was required for 53BP1 de-ADP-ribosylation, 53BP1 protein stability, and its function in cell survival. In summary, we demonstrate that NUDT16 regulates 53BP1 stability and 53BP1 recruitment at double-strand breaks, providing yet another mechanism of 53BP1 regulation.Significance: This study provides a novel mechanism of 53BP1 regulation by demonstrating that NUDT16 has hydrolase activities that remove ADP-ribosylation of 53BP1 to regulate 53BP1 stability and 53BP1 localization at DSBs.

中文翻译:

Nudix 水解酶 NUDT16 通过逆转 53BP1 ADP 核糖基化来调节 53BP1 蛋白。

53BP1 控制两条下游亚通路,一种由 PTIP 和 Artemis 介导,另一种由 RIF1 和 MAD2L2/Shieldin 介导,以协调 DNA 修复途径的选择。然而,DNA 修复中 53BP1 功能的上游调节因子仍然未知。我们和其他人最近报道了 TIRR 与 53BP1 结合以稳定它并通过阻断 53BP1 Tudor 结构域与 H4K20me2 位点的结合来防止 53BP1 定位到 DNA 损伤位点。在这里,我们报告了 Nudix 水解酶 NUDT16(一种 TIRR 同源物)调节 53BP1 的稳定性。我们通过 ADP 核糖基化鉴定了 53BP1 的一种新型翻译后修饰,该修饰由 PAR 结合 E3 泛素连接酶 RNF146 靶向,导致 53BP1 多泛素化和降解。作为对 DNA 损伤的反应,ADP 核糖基化的 53BP1 显着增加,导致其泛素化和降解。这些数据表明,NUDT16 在正常生长条件下和 DNA 损伤期间在控制 53BP1 水平中起主要作用。值得注意的是,NUDT16 催化失活突变体的过表达阻止了 53BP1 定位到双链断裂,因为(i)IR 后突变体与 TIRR 的结合增加;(ii) 突变体增强了 53BP1 Tudor 结构域与 TIRR 的结合,(iii) 突变体削弱了 53BP1 Tudor 结构域与 H4K20me2 的相互作用。此外,NUDT16 的催化水解酶活性是 53BP1 去 ADP 核糖基化、53BP1 蛋白稳定性及其在细胞存活中的功能所必需的。总之,我们证明了 NUDT16 在双链断裂处调节 53BP1 稳定性和 53BP1 募集,提供了另一种 53BP1 调节机制。意义:
更新日期:2020-03-02
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