Measuring ubiquitin chain linkage: Rap80 uses a molecular ruler mechanism for ubiquitin linkage specificity.
Measuring ubiquitin chain linkage: Rap80 uses a molecular ruler mechanism for ubiquitin linkage specificity.
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测量泛素链连接：Rap80 使用分子标尺机制来测量泛素连接特异性。
DOI：
10.1038/emboj.2009.221
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Chen,Xiang
中科院分区：
文献类型：
--
作者：
Walters,KylieJ;Chen,Xiang
DNA双链断裂导致Rnf 8-Ubc 13复合物募集到损伤位点，在那里它们催化K63连接的泛素化。受体相关蛋白80（Rap 80）随后结合K63连接的链，并带来BRCA 1复合物。Sato等人（2009）解析了Rap 80-UIM 1-UIM 2：K63连接的双泛素复合物的晶体结构，以显示连续螺旋跨越UIM 1-UIM 2区域，并限定了两个UIM的相对取向，以最佳地结合K63连接的链。这项研究提供了重要的见解，蛋白质泛素化如何触发特定的下游signalingevents.Cells安装一个多方面的反应，涉及转录控制，DNA修复机制和细胞周期调控的遗传毒性损伤。这些事件的排列依赖于翻译后修饰，这些修饰扩展靶蛋白的功能或控制其细胞丰度。泛素化用于这两个目的，其在DNA损伤反应中的许多基本功能的机械细节正在受到严格的审查。底物可以是单泛素化的或多泛素化的，其中多个泛素直接连接到底物或连续连接到先前连接的泛素，从而构建链。泛素有七个赖氨酸，为链长和连接多样性创造了机会。DNA损伤反应使用多种遍在蛋白信号机制来传达下游事件。在参与损伤诱导的细胞周期停滞的蛋白质上产生K48连接链，以促进其降解，从而限制其有效性的持续时间;该过程控制Chk 1（Zhang et al，2005），其对于G2/M DNA损伤诱导的检查点至关重要。相比之下，增殖细胞核抗原（PCNA）的单泛素化遵循在DNA损伤位点处的复制停滞，并促进复制性DNA聚合酶替换为损伤耐受性DNA聚合酶（综述参见（Ulrich，2009））。
DNA double-stranded breaks lead to the recruitment of the Rnf8–Ubc13 complex to the damage site where they catalyse K63-linked ubiquitination. Receptor-associated protein 80 (Rap80) subsequently binds the K63-linked chains and brings with it a BRCA1 complex. Sato et al (2009) solve the crystal structure of the Rap80-UIM1-UIM2: K63-linked diubiquitin complex to show that a contiguous helix spans the UIM1-UIM2 region and defines the relative orientation of the two UIMs for optimal binding to K63-linked chains. This study provides important insights into how protein ubiquitination triggers specific downstream signalling events.Cells mount a multi-faceted response to genotoxic damage that involves transcriptional control, DNA repair machinery, and cell-cycle regulation. The arrangement of these events relies on post-translational modifications that expand the functionality of the target protein or control its cellular abundance. Ubiquitination is used for both of these purposes, and the mechanistic details of its many essential functions in DNA damage response are under intense scrutiny. Substrates can be monoubiquitinated or polyubiquitinated with multiple ubiquitins attached directly to the substrate or serially to previously attached ubiquitin, thereby building a chain. Ubiquitin has seven lysines, creating opportunities for chain length and linkage diversity. DNA damage response uses multiple ubiquitin signalling mechanisms to communicate downstream events. K48-linked chains are generated on proteins involved in damage-induced cell-cycle arrest to promote their degradation and, thereby, limit the duration of their efficacy; this process controls Chk1 (Zhang et al, 2005), which is essential for the G2/M DNA damage-induced checkpoint. By contrast, monoubiquitination of proliferating cell nuclear antigen (PCNA) follows replication stalling at DNA damage sites and promotes the replacement of replicative DNA polymerases for damage-tolerant ones (for review, see (Ulrich, 2009).