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首页> 美国卫生研究院文献>Protein Cell >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 antagonizes ubiquitination of proliferating cell nuclear antigen and regulates the recruitment of polymerase η in response to oxidative DNA damage

机译：NEDDylation拮抗增殖细胞核抗原的泛素化并调节聚合酶η对氧化性DNA损伤的响应

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摘要

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s13238-017-0455-x) contains supplementary material, which is available to authorized users.
机译：NEDDylation已显示参与DNA损伤途径，但是神经前体细胞的底物在发育中被下调8（NEDD8），而NEDDylation在DNA损伤应答（DDR）中的作用尚不清楚。跨病变合成（TLS）是一种损伤耐受机制，其中RAD18 / RAD6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为NEDD8的底物，并显示E3连接酶RAD18催化的PCNA NEDDylation拮抗其泛素化作用。另外，NEDP1充当PCNA的去NEDDylase，NEDP1缺失增强PCNA NEDDylation，但减少其泛素化。响应H2O2刺激，NEDP1与PCNA分离，而RAD18依赖性PCNA NEDDylation在泛素化后显着增加。 Ubc12基因敲除对NEDDylation的损害增强PCNA泛素化并促进PCNA-polη相互作用，而NEDD8过度表达或NEDP1缺失引起的NEDDylation上调可减少泛素化PCNA的过度积累，从而抑制PCNA-polη相互作用并阻止polη病灶形成。此外，Ubc12敲除降低了细胞对H2O2诱导的氧化应激的敏感性，但NEDP1缺失加剧了这种敏感性。总的来说，我们的研究阐明了NEDDylation在DDR中作为PCNA单泛素化和polη募集的调节剂的重要作用。电子补充材料本文的在线版本（doi：10.1007 / s13238-017-0455-x）包含补充材料，该材料是可供授权用户使用。

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