XRCC4 (X-ray repair cross-complementing 4) is a critical scaffolding protein in non-homologous end joining (NHEJ), the primary double-strand break (DSB) repair pathway in mammalian cells 1. XRCC4 functions as a structural component that stabilizes DNA ligase IV and facilitates assembly of the NHEJ machinery at DSB sites 2. The protein forms long helical filaments with XRCC4-like factor (XLF), creating a protective scaffold that aligns broken DNA ends for accurate ligation without requiring long DNA overhangs 2. XRCC4 additionally interacts with accessory factors including PAXX, which provide complementary advantages for DNA end synapsis 3. Beyond canonical NHEJ, XRCC4 undergoes caspase-3 cleavage during apoptosis, generating a cytoplasmic form that activates phospholipid scramblase activity of XKR4, promoting phosphatidylserine exposure on apoptotic cell surfaces [PubMed:33725486]. Dysfunction of XRCC4 impairs efficient DSB repair, contributing to genomic instability and disease. XRCC4 gene polymorphisms are associated with glioma susceptibility in human populations 4. In glioblastoma, therapeutic resistance correlates with elevated NHEJ activity through XRCC4-mediated mechanisms 5. Germline XRCC4 mutations cause short stature, microcephaly, and endocrine dysfunction, reflecting critical roles in developmental processes requiring precise DNA repair.