RNF168 Binds and Amplifies Ubiquitin Conjugates on Damaged Chromosomes to Allow Accumulation of Repair Proteins
RNF168 Binds and Amplifies Ubiquitin Conjugates on Damaged Chromosomes to Allow Accumulation of Repair Proteins
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DOI：
10.1016/j.cell.2008.12.041
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发表时间：
2009-02-06
期刊：
影响因子：
64.5
通讯作者：
Lukas, Claudia
中科院分区：
文献类型：
--
作者：
Doil, Carsten;Mailand, Niels;Lukas, Claudia
DNA双链断裂不仅会中断遗传信息，还会破坏染色质结构，这两种损伤都需要修复机制来保证基因组的完整性。我们之前表明，rnf8介导的染色质泛素化通过促进dsb修复因子的积累来保护基因组完整性。在这里，我们提供的证据表明，虽然RNF8是触发dsb相关泛素化的必要条件，但它不足以维持该隔室中的共轭泛素。我们发现RNF168是一种新的染色质相关泛素连接酶，具有结合泛素的能力。我们发现RNF168与泛素化的H2A相互作用，以rnf8依赖的方式在dsb上组装，并且通过靶向H2A和H2AX，将赖氨酸63连接的泛素偶联物的局部浓度放大到保留53BP1和BRCA1所需的阈值。因此，RNF168定义了一个涉及受损染色体上序列泛素化的新途径，并揭示了E3连接酶在基因组维持中的功能合作。
DNA double-strand breaks (DSBs) not only interrupt the genetic information, but also disrupt the chromatin structure, and both impairments require repair mechanisms to ensure genome integrity. We showed previously that RNF8-mediated chromatin ubiquitylation protects genome integrity by promoting the accumulation of repair factors at DSBs. Here, we provide evidence that, while RNF8 is necessary to trigger the DSB-associated ubiquitylations, it is not sufficient to sustain conjugated ubiquitin in this compartment. We identified RNF168 as a novel chromatin-associated ubiquitin ligase with an ability to bind ubiquitin. We show that RNF168 interacts with ubiquitylated H2A, assembles at DSBs in an RNF8-dependent manner, and, by targeting H2A and H2AX, amplifies local concentration of lysine 63-linked ubiquitin conjugates to the threshold required for retention of 53BP1 and BRCA1. Thus, RNF168 defines a new pathway involving sequential ubiquitylations on damaged chromosomes and uncovers a functional cooperation between E3 ligases in genome maintenance.