Graduate School of Frontier Biosciences, Osaka University, Yamadaoka 1-3, Suita, Osaka 565-0871, Japan.
Mol Cell Biol. 2010 Jun;30(11):2708-23. doi: 10.1128/MCB.01460-09. Epub 2010 Apr 5.
UV-damaged-DNA-binding protein (UV-DDB) is a heterodimer comprised of DDB1 and DDB2 and integrated in a complex that includes a ubiquitin ligase component, cullin 4A, and Roc1. Here we show that the ubiquitin ligase activity of the DDB2 complex is required for efficient global genome nucleotide excision repair (GG-NER) in chromatin. Mutant DDB2 proteins derived from xeroderma pigmentosum group E patients are not able to mediate ubiquitylation around damaged sites in chromatin. We also found that CSN, a negative regulator of cullin-based ubiquitin ligases, dissociates from the DDB2 complex when the complex binds to damaged DNA and that XPC and Ku oppositely regulate the ubiquitin ligase activity, especially around damaged sites. Furthermore, the DDB2 complex-mediated ubiquitylation plays a role in recruiting XPA to damaged sites. These findings shed some light on the early stages of GG-NER.
紫外线损伤 DNA 结合蛋白（UV-DDB）是一种由 DDB1 和 DDB2 组成的异二聚体，整合在一个包含泛素连接酶成分 Cullin 4A 和 Roc1 的复合物中。在这里，我们表明 DDB2 复合物的泛素连接酶活性对于染色质中有效的全基因组核苷酸切除修复（GG-NER）是必需的。源自着色性干皮病组 E 患者的突变 DDB2 蛋白不能介导染色质中受损部位的泛素化。我们还发现，当复合物与受损 DNA 结合时，CSN（一种基于 Cullin 的泛素连接酶的负调节剂）从 DDB2 复合物中解离，并且 XPC 和 Ku 相反地调节泛素连接酶活性，特别是在受损部位周围。此外，DDB2 复合物介导的泛素化在将 XPA 募集到受损部位中起作用。这些发现为 GG-NER 的早期阶段提供了一些线索。
