DNA ligase 4 (LIG4)

DNA ligase 4 is an **ATP-dependent DNA ligase** essential for joining DNA double-strand breaks (DSBs) through the classical nonhomologous end-joining (NHEJ) pathway, a critical process for DNA repair and immune system development[1][2][3]. It functions by catalyzing the final sealing of DNA nicks, restoring DNA integrity after damage or recombination. DNA ligase 4 operates as part of a multi-protein complex (including XRCC4 and DNA-PK) and is mechanistically flexible, able to ligate a range of DNA ends, including those with compatible overhangs, microhomology, and even damaged bases with reduced fidelity[1][2][3]. Dysfunction or mutation of DNA ligase 4 results in "LIG4 syndrome," a constellation of disorders involving immunodeficiency, microcephaly, growth delay, and increased cancer susceptibility, reflecting its central role in genome maintenance[1][2]. DNA ligase 4 is structurally distinct within the ligase family, possessing unique domains and regulatory interactions that tune its repair activity and fidelity[1][3]. While not a current target of approved therapeutics, it represents a conceptual candidate for synthetic lethality in oncology, though safety concerns substantially limit direct inhibition outside experimental settings[2].

Other names

DNA ligase IVPolydeoxyribonucleotide synthase [ATP] 4Polynucleotide ligaseSealaseDNA repair enzymeDNA joinaseLIG4S

Ligase inhibitors (experimental): inhibition of ATP-dependent DNA joining, leading to impaired DNA double-strand break repair and cell death[2]. Potential synthetic lethality strategies in cancers with DSB repair defects. Viral manipulation: hijacking Lig4 activity for viral genome integration and replication[1].