DNA ligase 4 (LIG4) (LIG4)

DNA ligase 4 (LIG4) is a critical enzyme in the non-homologous end joining (NHEJ) pathway, which is the primary mechanism for repairing DNA double-strand breaks in eukaryotic cells [1, 2]. It functions by forming a stable complex with XRCC4 and XLF to catalyze the final ligation step, sealing broken DNA ends to maintain genomic integrity [1, 3]. Beyond general DNA repair, LIG4 is essential for V(D)J recombination, a process vital for the development of a diverse immune repertoire [2, 4]. Mutations in the LIG4 gene lead to LIG4 syndrome, a rare condition characterized by severe immunodeficiency, microcephaly, and extreme sensitivity to ionizing radiation [3, 5]. In oncology, LIG4 is an attractive therapeutic target; its inhibition can sensitize cancer cells to DNA-damaging agents like radiotherapy and chemotherapy [6, 7]. Small molecule inhibitors such as SCR7 are being explored to enhance the efficacy of these treatments and to improve the precision of CRISPR-Cas9 genome editing by shifting repair toward homology-directed repair (HDR) [7, 8]. The enzyme's role in maintaining the genome makes it a double-edged sword, as its deficiency promotes malignancy while its overexpression can lead to treatment resistance [6]. Consequently, LIG4 modulators are emerging as potential tools in the treatment of various diseases, particularly aggressive cancers [6].

Other names

DNA ligase IVLIG4LIG4SDNA ligase 4

Inhibition of DNA ligase IV enzymatic activity, specifically blocking the non-homologous end joining (NHEJ) pathway for DNA double-strand break repair [6, 8].