RNF219 RING Finger Domain Mutants Drive Phase Separation to Encapsulate CCR4‐NOT and Promote Cell Proliferation

ABSTRACT RING finger protein 219 (RNF219) is a co‐factor for the CCR4‐NOT deadenylase complex in mammals. Here, we found that mutations within the C3HC4 scaffold of the RING finger domain in RNF219 are capable of forming condensates via liquid–liquid phase separation (LLPS), though the wild‐type RING finger domain intrinsically suppresses LLPS. We further demonstrated that the adjacent coiled‐coil 1 (CC1) domain promotes the potential of RNF219 to form condensates. Moreover, the mutant RNF219 condensates are able to encapsulate the CCR4‐NOT complex, inhibiting the RNA deadenylation activity of CCR4‐NOT. Additionally, we observed that RNF219 mutations could promote cell proliferation. These findings suggest a pathogenic mechanism whereby RNF219 mutations could induce CCR4‐NOT condensate formation, inhibit deadenylation‐dependent mRNA decay and drive cell proliferation.