NEDDylation antagonizes ubiquitination of proliferating cell nuclear antigen and regulates the recruitment of polymerase η in response to oxidative DNA damage.
NEDDylation antagonizes ubiquitination of proliferating cell nuclear antigen and regulates the recruitment of polymerase η in response to oxidative DNA damage.
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NEDDylation 拮抗增殖细胞核抗原的泛素化并调节聚合酶 eta 的募集以响应氧化 DNA 损伤
DOI：
10.1007/s13238-017-0455-x
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发表时间：
2018-04
期刊：
影响因子：
21.1
通讯作者：
Zheng X
中科院分区：
文献类型：
--
作者：
Guan J;Yu S;Zheng X
NEDD化已被证明参与DNA损伤途径，但神经前体细胞发育下调表达蛋白8（NEDD 8）的底物以及NEDD化在DNA损伤反应（DDR）中的作用在很大程度上是未知的。翻译合成（TLS）是一种损伤耐受机制，其中RAD 18/RAD 6介导的单泛素化增殖细胞核抗原（PCNA）促进聚合酶η（polη）的募集以绕过病变。在这里，我们确定PCNA作为底物的NEDD 8，并显示E3连接酶RAD 18催化的PCNA NEDD化拮抗其泛素化。此外，NEDP 1作为PCNA的去NEDD酶，并且NEDP 1缺失增强PCNA NEDD化，但降低其泛素化。在H2 O2刺激下，NEDP 1与PCNA分离，并且在其泛素化后，RAD 18依赖的PCNA NEDD化显著增加。Ubc 12基因敲除可抑制NEDD化，增强PCNA泛素化，促进PCNA与pol η的相互作用;而NEDD 8基因过表达或NEDP 1基因缺失可抑制PCNA泛素化，从而抑制PCNA与pol η的相互作用，阻断polη灶的形成。此外，Ubc 12基因敲除降低了细胞对H2 O2诱导的氧化应激的敏感性，但NEDP 1基因缺失则增强了这种敏感性。总的来说，我们的研究阐明了NEDD化在DDR中作为PCNA单泛素化和polη募集的调节剂的重要作用。本文的在线版本（doi：10.1007/s13238-017-0455-x）包含补充材料，可供授权用户使用。
NEDDylation has been shown to participate in the DNA damage pathway, but the substrates of neural precursor cell expressed developmentally downregulated 8 (NEDD8) and the roles of NEDDylation involved in the DNA damage response (DDR) are largely unknown. Translesion synthesis (TLS) is a damage-tolerance mechanism, in which RAD18/RAD6-mediated monoubiquitinated proliferating cell nuclear antigen (PCNA) promotes recruitment of polymerase η (polη) to bypass lesions. Here we identify PCNA as a substrate of NEDD8, and show that E3 ligase RAD18-catalyzed PCNA NEDDylation antagonizes its ubiquitination. In addition, NEDP1 acts as the deNEDDylase of PCNA, and NEDP1 deletion enhances PCNA NEDDylation but reduces its ubiquitination. In response to H2O2 stimulation, NEDP1 disassociates from PCNA and RAD18-dependent PCNA NEDDylation increases markedly after its ubiquitination. Impairment of NEDDylation by Ubc12 knockout enhances PCNA ubiquitination and promotes PCNA-polη interaction, while up-regulation of NEDDylation by NEDD8 overexpression or NEDP1 deletion reduces the excessive accumulation of ubiquitinated PCNA, thus inhibits PCNA-polη interaction and blocks polη foci formation. Moreover, Ubc12 knockout decreases cell sensitivity to H2O2-induced oxidative stress, but NEDP1 deletion aggravates this sensitivity. Collectively, our study elucidates the important role of NEDDylation in the DDR as a modulator of PCNA monoubiquitination and polη recruitment. The online version of this article (doi:10.1007/s13238-017-0455-x) contains supplementary material, which is available to authorized users.
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影响因子：
14.9
作者：
Jimeno S;Fernández-Ávila MJ;Cruz-García A;Cepeda-García C;Gómez-Cabello D;Huertas P
通讯作者：
Huertas P
影响因子：
7.7
作者：
Hedglin, Mark;Pandey, Binod;Benkovic, Stephen J.
通讯作者：
Benkovic, Stephen J.
RAD18 传递 DNA 损伤信号以引发同源重组修复。
影响因子：
21.3
作者：
Huang, Jun;Huen, Michael S. Y.;Kim, Hongtae;Leung, Charles Chung Yun;Glover, J. N. Mark;Yu, Xiaochun;Chen, Junjie
通讯作者：
Chen, Junjie
影响因子：
8.8
作者：
Brown JS;Lukashchuk N;Sczaniecka-Clift M;Britton S;le Sage C;Calsou P;Beli P;Galanty Y;Jackson SP
通讯作者：
Jackson SP
Neddylation 抑制剂 MLN4924 抑制人胃癌细胞的生长和迁移
影响因子：
4.6
作者：
Lan H;Tang Z;Jin H;Sun Y
通讯作者：
Sun Y