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损伤应答（DDR）对于维持基因组的稳定性和保护细胞免于癌变是至关重要的。泛素化和类泛素化修饰从DNA损伤的信号传递到DNA修复的过程中都发挥着重要作用。在本研究中，我们发现E3连接酶环指蛋白126（RNF126）以RNF8依赖的方式被募集到紫外激光微辐射诱导的DNA损伤条带中。RNF126与另一个E3连接酶RNF168发生直接相互作用，并且对RNF168进行泛素化修饰。过表达野生型RNF126，而不是催化失活突变型RNF126(CC229/232AA)，减少了H2A组蛋白家族成员X(H2AX)的泛素化修饰，以及随后博莱霉素诱导的FK2、53BP1和RAP80的聚焦形成。有趣的是，过表达和抑制RNF126都不利于同源重组（HR）介导的DNA双链断裂（DSB）的修复。总之，我们的研究结果表明RNF126在DNA损伤应答反应中负性调节RNF168的功能，其适当的细胞表达水平对于同源重组介导的DNA双链断裂（DSB）修复是必需的。





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