XRCC5 (Ku80) is a DNA-binding protein essential for double-strand break (DSB) repair through classical non-homologous end joining (NHEJ) 1. It forms a Ku70:Ku80 heterodimer that binds DSB ends and recruits repair factors to assemble the core NHEJ complex, facilitating broken DNA ligation 1. XRCC5 also possesses 5'-deoxyribose-5-phosphate lyase activity, cleaning abasic site termini to prepare DNA ends for ligation. Beyond DSB repair, XRCC5 contributes to V(D)J recombination, enabling antibody and T-cell receptor diversity generation 1. The protein participates in telomere maintenance and transcriptional regulation as a cofactor, and assists in innate immune responses by facilitating IRF3 phosphorylation through the HDP-RNP complex. Additionally, XRCC5 binds cellular RNAs and recruits DNA-dependent protein kinase to facilitate ribosomal RNA biogenesis. Disease relevance is substantial: XRCC5 polymorphisms (rs3835 G>A, rs828907 G>T) are associated with increased breast cancer risk 2, and genetic variation in XRCC5 influences alcohol dependence susceptibility 3. In colorectal cancer, DCLK1-mediated phosphorylation of XRCC5 activates COX2 transcription, promoting cancer stemness and inflammation 4. These findings highlight XRCC5's dual role in genomic stability and disease pathogenesis, with potential therapeutic implications for cancer and other disorders.