PAXX (PAXX non-homologous end joining factor) is a non-essential DNA repair protein that functions as a structural facilitator in classical non-homologous end joining (NHEJ), the primary double-strand break (DSB) repair pathway in mammalian cells 1. PAXX acts as a scaffold protein that promotes the assembly and stability of the NHEJ machinery by binding to the Ku70/Ku80 heterodimer at DSB sites 2. It collaborates with XLF and DNA polymerase lambda to facilitate ligation of non-cohesive DNA ends and blunt-ended DNA termini 1. Structurally, PAXX binds to the Ku heterodimer through its C-terminal Ku-binding motif and can simultaneously interact with XLF to form alternate DNA-dependent protein kinase dimers, providing complementary advantages for DNA end synapsis 2. Notably, PAXX and XLF possess distinct but overlapping functions; PAXX specifically stabilizes repair complex assembly for DSBs requiring end processing, making the PAXX-Ku interaction rate-limiting for repair completion 3. Beyond DNA repair, PAXX contributes to antiviral immunity by restricting herpesvirus 1 infection 4. Clinically, elevated PAXX expression drives chemoresistance in osteosarcoma through enhanced NHEJ efficiency; disrupting the PAXX-Ku70 interaction re-sensitizes resistant tumors to doxorubicin and cisplatin 5.