RNF169 is a non-canonical E3 ubiquitin-protein ligase that regulates DNA double-strand break (DSB) repair pathway choice 1. Rather than catalyzing ubiquitylation itself, RNF169 functions as a ubiquitin reader that recognizes RNF168-mediated ubiquitin modifications on DSB-containing chr11 1. Upon recruitment to DSB sites, RNF169 competitively displaces 53BP1 and RAP80-BRCA1 from RNF168-modified chr11 independent of its E3 ligase activity, thereby promoting homologous recombination repair (HRR) and single-strand annealing while restraining non-homologous end joining (NHEJ) 12. RNF169 exhibits preferential accumulation at resected DNA ends and promotes CtIP-dependent DSB end resection 2. Beyond DSB repair, RNF169 functions as a reader of H2BK120ub at replication forks, protecting nascent DNA from nucleolytic degradation during replication stress 3. RNF169 protein stability is maintained through a dual-function nuclear localization signal that mediates direct interaction with deubiquitylase USP7 4. Dysregulation of RNF169 has clinical implications, as altered expression correlates with breast cancer outcomes 4, and RNF169 is targeted for epigenetic silencing by phytoestrogen-induced pathways in mammary epithelial cells 5.