DNA ligase 3 (LIG3) (LIG3)

DNA ligase 3 (LIG3) is a critical enzyme involved in multiple DNA repair pathways, including base excision repair (BER) and the error-prone alternative non-homologous end joining (alt-NHEJ) pathway. It is uniquely essential for the maintenance of mitochondrial DNA integrity, as it is the only DNA ligase present within the mitochondria (PubMed: 21822276). In the nucleus, LIG3 typically functions in a constitutive complex with the scaffolding protein XRCC1 to repair single-strand breaks. In oncology, LIG3 is frequently overexpressed in certain malignancies, such as chronic myeloid leukemia and multiple myeloma, where it provides a survival advantage by compensating for deficiencies in primary repair pathways like homologous recombination (PubMed: 28601448). Therapeutic targeting of LIG3, through small molecule inhibitors or mRNA-directed approaches like siRNA, is being explored as a strategy for synthetic lethality, particularly in tumors with BRCA1/2 mutations or those resistant to PARP inhibitors (PubMed: 22307177). However, the essential role of LIG3 in mitochondrial function presents a significant challenge for drug development due to the risk of systemic mitochondrial toxicity in healthy tissues.

Other names

DNA ligase IIILIG3Polydeoxyribonucleotide synthase [ATP] 3

Inhibition of DNA ligation and repair, induction of synthetic lethality in DNA repair-deficient cells, and degradation of mRNA via RNA interference.