LIG3 encodes DNA ligase 3, a critical enzyme with distinct functions in nuclear and mitochondrial DNA repair. The gene produces multiple isoforms, with isoform 1 functioning as the only mitochondrial DNA ligase essential for mitochondrial base-excision repair, while isoform 3 operates in the nucleus as a heterodimer with XRCC1 to repair DNA strand breaks 1. LIG3 plays a crucial role in alternative non-homologous end joining (alt-NHEJ) pathway for double-strand break repair, particularly when the major DNA ligase IV-dependent pathway is defective 1. The enzyme is essential for replication-associated nick ligation, especially at 5'-phosphorylated nicks between Okazaki fragments, working alongside ligase 1 in this process 2. LIG3 also contributes to extrachromosomal DNA (ecDNA) formation and maintenance through DNA end ligation mechanisms 34. Clinical significance includes its frequent overexpression in cancer cells, serving as a biomarker for increased dependence on alternative NHEJ and representing a promising therapeutic target 1. Genetic variations in LIG3 have been associated with gastric cancer risk and corneal dystrophies 56. The protein's dysfunction can lead to severe developmental defects, as demonstrated by lethal anemia in mouse models with catalytically inactive PARP2, highlighting LIG3's critical role in erythropoiesis 2.