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首页> 外文期刊>Cell cycle >A small ubiquitin binding domain inhibits ubiquitin-dependent protein recruitment to DNA repair foci
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A small ubiquitin binding domain inhibits ubiquitin-dependent protein recruitment to DNA repair foci

机译：一个小的泛素结合结构域抑制泛素依赖性蛋白募集至DNA修复灶

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The rapid ubiquitination of chromatin surrounding DNA double-stranded breaks (DSB) drives the formation of large structures called ionizing radiation-induced foci (IRIF), comprising many DNA damage response (DDR) proteins. This process is regulated by RNF8 and RNF168 ubiquitin ligases and is thought to be necessary for DNA repair and activation of signaling pathways involved in regulating cell cycle checkpoints. Here we demonstrate that it is possible to interfere with ubiquitin-dependent recruitment of DDR factors by expressing proteins containing ubiquitin binding domains (UBDs) that bind to lysine 63-linked polyubiquitin chains. Expression of the E3 ubiquitin ligase RAD18 prevented chromatin spreading of 53BP1 at DSBs, and this phenomenon was dependent upon the integrity of the RAD18 UBD. An isolated RAD18 UBD interfered with 53BP1 chromatin spreading, as well as other important DDR mediators, including RAP80 and the BRCA1 tumor suppressor protein, consistent with the model that the RAD18 UBD is blocking access of proteins to ubiquitinated chromatin. Using the RAD18 UBD as a tool to impede localization of 53BP1 and BRCA1 to repair foci, we found that DDR signaling, DNA DSB repair, and radiosensitivity were unaffected. We did find that activated ATM (S1981P) and phosphorylated SMC1 (a specific target of ATM) were not detectable in DNA repair foci, in addition to upregulated homologous recombination repair, revealing 2 DDR responses that are dependent upon chromatin spreading of certain DDR factors at DSBs. These data demonstrate that select UBDs containing targeting motifs may be useful probes in determining the biological significance of protein-ubiquitin interactions.
机译：围绕DNA双链断裂（DSB）的染色质的快速泛素化驱动了称为电离辐射诱导病灶（IRIF）的大型结构的形成，该结构包含许多DNA损伤反应（DDR）蛋白。此过程由RNF8和RNF168泛素连接酶调节，被认为对于DNA修复和涉及调节细胞周期检查点的信号通路的激活是必需的。在这里，我们证明有可能通过表达含有与赖氨酸63连接的多泛素链结合的泛素结合域（UBD）的蛋白质来干扰DDR因子的泛素依赖性依赖募集。 E3泛素连接酶RAD18的表达阻止了53BP1在DSB上的染色质扩散，这种现象取决于RAD18 UBD的完整性。分离的RAD18 UBD干扰了53BP1染色质的扩散，以及其他重要的DDR介体，包括RAP80和BRCA1肿瘤抑制蛋白，与RAD18 UBD阻止蛋白质接近泛素化染色质的模型相一致。使用RAD18 UBD作为阻止53BP1和BRCA1定位以修复灶的定位的工具，我们发现DDR信号传导，DNA DSB修复和放射敏感性均不受影响。我们确实发现，除了上调的同源重组修复外，在DNA修复灶中也未检测到活化的ATM（S1981P）和磷酸化的SMC1（ATM的特定靶标），揭示了2个DDR反应，这些反应取决于某些DDR因子在染色质上的扩散。 DSB。这些数据表明，含有靶向基序的选定UBD可能是确定蛋白质-泛素相互作用的生物学意义的有用探针。

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