LIG4 encodes DNA ligase IV, an essential enzyme that catalyzes the final ligation step in non-homologous end joining (NHEJ), the primary pathway for repairing DNA double-strand breaks in mammalian cells 1. LIG4 forms a functional complex with XRCC4 and operates within a flexible ω-shaped framework composed of XRCC4 and XLF, where it coordinates with DNA polymerase μ to complete gap filling and end joining 1. The enzyme exhibits mechanistic flexibility, ligating nicks and compatible DNA overhangs alone, and can ligate ends with microhomology and gaps when complexed with XRCC4 1. Beyond DNA repair, LIG4 plays a crucial role in V(D)J recombination during immune system development. Mutations in LIG4 cause LIG4 syndrome, a rare autosomal recessive disorder characterized by microcephaly, growth retardation, immunodeficiency, radiosensitivity, and pancytopenia 2. The syndrome requires at least one hypomorphic allele for viability, as complete loss of LIG4 function is embryonically lethal 2. Recent studies have also implicated LIG4 in extrachromosomal circular DNA (ecDNA) biogenesis, where it mediates cancer drug resistance by enabling ecDNA-driven adaptation 3.