College of Life Sciences, Capital Normal University, Beijing 100048, China; Faculty of Life Sciences, Tangshan Normal College, Tangshan 063000, China.
College of Life Sciences, Capital Normal University, Beijing 100048, China.
Genomics Proteomics Bioinformatics. 2018 Dec;16(6):428-438. doi: 10.1016/j.gpb.2018.07.004. Epub 2018 Dec 4.
DNA damage response (DDR) is essential for maintaining genome stability and protecting cells from tumorigenesis. Ubiquitin and ubiquitin-like modifications play an important role in DDR, from signaling DNA damage to mediating DNA repair. In this report, we found that the E3 ligase ring finger protein 126 (RNF126) was recruited to UV laser micro-irradiation-induced stripes in a RNF8-dependent manner. RNF126 directly interacted with and ubiquitinated another E3 ligase, RNF168. Overexpression of wild type RNF126, but not catalytically-inactive mutant RNF126 (CC229/232AA), diminished ubiquitination of H2A histone family member X (H2AX), and subsequent bleomycin-induced focus formation of total ubiquitin FK2, TP53-binding protein 1 (53BP1), and receptor-associated protein 80 (RAP80). Interestingly, both RNF126 overexpression and RNF126 downregulation compromised homologous recombination (HR)-mediated repair of DNA double-strand breaks (DSBs). Taken together, our findings demonstrate that RNF126 negatively regulates RNF168 function in DDR and its appropriate cellular expression levels are essential for HR-mediated DSB repair.
DNA 损伤反应（DDR）对于维持基因组稳定性和保护细胞免受肿瘤发生至关重要。泛素和泛素样修饰在 DDR 中起着重要作用，从信号转导 DNA 损伤到介导 DNA 修复。在本报告中，我们发现 E3 连接酶环指蛋白 126（RNF126）以 RNF8 依赖的方式被招募到 UV 激光微照射诱导的条带中。RNF126 直接与另一个 E3 连接酶 RNF168 相互作用并泛素化 RNF168。野生型 RNF126 的过表达，但不是催化失活突变体 RNF126（CC229/232AA），减少了组蛋白家族成员 X（H2AX）的泛素化，随后导致博来霉素诱导的总泛素 FK2、TP53 结合蛋白 1（53BP1）和受体相关蛋白 80（RAP80）焦点形成。有趣的是，RNF126 的过表达和下调都损害了同源重组（HR）介导的 DNA 双链断裂（DSB）修复。总之，我们的研究结果表明，RNF126 负调控 DDR 中 RNF168 的功能，其适当的细胞表达水平对于 HR 介导的 DSB 修复至关重要。
