Ring finger protein 169 (RNF169)

Ring finger protein 169 (RNF169) is an E3 ubiquitin-protein ligase involved in the cellular response to DNA double-strand breaks. RNF169 is recruited to sites of DNA damage via recognition of ubiquitylated histone H2A (catalyzed by another E3 ligase, RNF168), where it binds through multiple interaction motifs. Unlike canonical E3 ligase activity, RNF169 primarily acts as a competitive inhibitor, limiting the accumulation of repair mediators such as 53BP1 and RAP80 at damaged chromatin[3][4][7]. By suppressing certain pathways (notably non-homologous end joining) and promoting others (homologous recombination), RNF169 fine-tunes the cell’s choice of double-strand break repair mechanism to maintain genomic integrity[1][3]. Dysregulation of RNF169 expression or function can contribute to cancer progression and impact responses to DNA damage–targeted therapies, such as PARP inhibitors[1][7]. RNF169 itself is not typically targeted by drugs, but its activity modulates cellular responses to DNA damage and may provide insight into new therapeutic strategies or act as a biomarker in cancers associated with defective DNA repair pathways[1][7].

Other names

E3 ubiquitin-protein ligase RNF169KIAA1991RING-type E3 ubiquitin transferase RNF169RN169 protein

Not directly targeted by approved drugs. Loss or inhibition of RNF169 increases sensitivity to PARP inhibitors by destabilizing high-fidelity double-strand break repair, but there are no selective RNF169 modulators in clinical use[1].