DNA ligase 3 (DNA ligase III (LIG3))

DNA ligase 3 is a vertebrate-specific enzyme crucial for sealing nicks in DNA during replication and multiple DNA repair pathways, including base excision, nucleotide excision, and single-strand break repair in both nuclear and mitochondrial compartments. Its structure features a unique N-terminal zinc finger that enhances DNA end recognition and binding. In the nucleus, it operates mainly as a complex with XRCC1, and in mitochondria, it is essential for genome maintenance. Ligase 3 becomes particularly important in cells where canonical NHEJ is impaired, facilitating an alternative repair pathway. It is frequently overexpressed in various cancers, where it promotes survival by maintaining DNA repair capacity, making it a promising therapeutic target.

Other names

LIG3DNA ligase IIIDNA ligase IIIα (nuclear and mitochondrial isoforms)Ligase III

Inhibitors would block the catalytic activity of DNA ligase 3, preventing DNA strand rejoining and leading to accumulation of DNA strand breaks, genomic instability, and cell death, especially in cancer cells dependent on alternative NHEJ. Potential for synthetic lethality when combined with inhibitors of other DNA repair proteins.