RNF168 is an E3 ubiquitin ligase essential for DNA damage response and repair. Structurally, RNF168 contains an intrinsically disordered region (amino acids 460-550) that enables liquid-liquid phase separation (LLPS) 1. Functionally, RNF168 catalyzes Lys-63-linked polyubiquitination of histone H2A/H2AX at double-strand breaks (DSBs) and interstrand crosslinks, promoting recruitment of repair factors TP53BP1 and BRCA1 2. K63-linked polyubiquitin chains enhance RNF168 condensation, creating a positive feedback loop that amplifies repair efficiency 1. RNF168 activity is tightly regulated: SUMOylation by ZNF451 stabilizes RNF168 accumulation at damage sites 3, while SENP1-mediated deSUMOylation prevents excessive phase separation and promotes repair 4. HDAC6 negatively regulates RNF168-H2A/H2AX interaction until RNF168-catalyzed ubiquitination triggers HDAC6 degradation 2. Clinically, mutations in RNF168 cause RIDDLE syndrome 5, and RNF168 dysregulation associates with Crohn's disease fibrosis 6 and premature ovarian insufficiency 7. These findings suggest RNF168 represents a therapeutic target for cancer radiotherapy and DNA damage-related diseases.