LIG4

LIG4, or DNA ligase IV, is a gene that encodes the DNA ligase IV enzyme, a member of the ligase family responsible for sealing breaks in the DNA backbone during non-homologous end joining (NHEJ). DNA ligase IV is primarily a nuclear enzyme that forms a stable complex with XRCC4 and, in some contexts, with XLF/Cernunnos. The LIG4-XRCC4 complex, together with the Ku70/Ku80 heterodimer and other NHEJ factors, processes and ligates DNA ends that arise from ionizing radiation, oxidative damage, or during V(D)J recombination in developing lymphocytes. The enzyme contains an N-terminal catalytic domain and C-terminal BRCT repeats that mediate protein interactions and localization.

In vertebrates, ligase IV activity is essential for V(D)J recombination, which generates diverse antigen receptors, and for the general repair of DNA double-strand breaks. Deficiency of LIG4 disrupts these processes and leads to genomic instability.

Clinically, LIG4 deficiency is a rare autosomal recessive disorder characterized by severe radiosensitivity, developmental delay, microcephaly, growth retardation, and varying immunodeficiency. Patients often experience recurrent infections and may present with autoimmunity or auto-inflammatory features. The condition reflects the vital role of ligase IV in maintaining genome integrity, especially in lymphocytes during antigen receptor assembly.

Research utilizing knockout and hypomorphic mouse models has helped delineate the enzyme’s role in development, DNA repair, and immune function, and informs studies of cancer susceptibility and radiation response.