Stewart Grant S, Panier Stephanie, Townsend Kelly, Al-Hakim Abdallah K, Kolas Nadine K, Miller Edward S, Nakada Shinichiro, Ylanko Jarkko, Olivarius Signe, Mendez Megan, Oldreive Ceri, Wildenhain Jan, Tagliaferro Andrea, Pelletier Laurence, Taubenheim Nadine, Durandy Anne, Byrd Philip J, Stankovic Tatjana, Taylor A Malcolm R, Durocher Daniel
Cancer Research UK, Institute for Cancer Studies, University of Birmingham, Edgbaston, Birmingham, UK.
Cell. 2009 Feb 6;136(3):420-34. doi: 10.1016/j.cell.2008.12.042.
The biological response to DNA double-strand breaks acts to preserve genome integrity. Individuals bearing inactivating mutations in components of this response exhibit clinical symptoms that include cellular radiosensitivity, immunodeficiency, and cancer predisposition. The archetype for such disorders is Ataxia-Telangiectasia caused by biallelic mutation in ATM, a central component of the DNA damage response. Here, we report that the ubiquitin ligase RNF168 is mutated in the RIDDLE syndrome, a recently discovered immunodeficiency and radiosensitivity disorder. We show that RNF168 is recruited to sites of DNA damage by binding to ubiquitylated histone H2A. RNF168 acts with UBC13 to amplify the RNF8-dependent histone ubiquitylation by targeting H2A-type histones and by promoting the formation of lysine 63-linked ubiquitin conjugates. These RNF168-dependent chromatin modifications orchestrate the accumulation of 53BP1 and BRCA1 to DNA lesions, and their loss is the likely cause of the cellular and developmental phenotypes associated with RIDDLE syndrome.
对DNA双链断裂的生物学反应有助于维持基因组完整性。在该反应的组成成分中携带失活突变的个体表现出包括细胞放射敏感性、免疫缺陷和癌症易感性在内的临床症状。这类疾病的典型代表是由DNA损伤反应的核心成分ATM双等位基因突变引起的共济失调毛细血管扩张症。在此，我们报道泛素连接酶RNF168在RIDDLE综合征中发生突变，RIDDLE综合征是一种最近发现的免疫缺陷和放射敏感性疾病。我们表明，RNF168通过与泛素化的组蛋白H2A结合而被招募到DNA损伤位点。RNF168与UBC13共同作用，通过靶向H2A类型的组蛋白并促进赖氨酸63连接的泛素缀合物的形成来放大RNF8依赖性的组蛋白泛素化。这些依赖RNF168的染色质修饰协调了53BP1和BRCA1在DNA损伤处的积累，而它们的缺失可能是与RIDDLE综合征相关的细胞和发育表型的原因。
