DNA 磷酸二酯骨架的断裂修复对基因组的完整性至关重要。断裂在正常过程中产生，例如 DNA 复制、细胞分化过程中的胞嘧啶去甲基化、免疫系统的基因重排和生殖细胞发育。此外，它们直接由 DNA 损伤剂引起或间接由修复过程中的损伤切除引起。断裂由 DNA 连接酶连接，该酶在 DNA 推歧口附近的 3' 羟基和 5' 磷酸末端催化磷酸二酯键的形成。三个人类基因编码依赖 ATP 的 DNA 连接酶。这些酶具有保守的催化核心，由三个亚域包围连接时的断裂双链 DNA。DNA 连接酶通过特定的蛋白质相互作用定位到不同的核 DNA 事务中。DNA 连接酶 IIIα 和 DNA 连接酶 IV 分别与 DNA 修复蛋白 XRCC1 和 XRCC4 形成稳定的复合物。DNA 连接酶 I 和 DNA 连接酶 IIIα 在 DNA 复制、切除修复和单链断裂修复中具有功能冗余。虽然 DNA 连接酶 IV 是主要的双链断裂修复途径非同源末端连接的核心成分，但其他酶参与次要的、替代的双链断裂修复途径。与细胞核相比，只有 DNA 连接酶 IIIα 存在于线粒体中，并且对维持线粒体基因组至关重要。已描述了由 LIG1 或 LIG4 突变引起的人类免疫缺陷综合征。DNA 连接酶抑制剂的临床前研究已经确定了癌细胞中可靶向的异常和 DNA 连接酶作为癌症治疗的潜在靶点的证据。版权所有 © 2023 Elsevier Ltd. 保留所有权利。

The joining of breaks in the DNA phosphodiester backbone is essential for genome integrity. Breaks are generated during normal processes such as DNA replication, cytosine demethylation during differentiation, gene rearrangement in the immune system and germ cell development. In addition, they are generated either directly by a DNA damaging agent or indirectly due to damage excision during repair. Breaks are joined by a DNA ligase that catalyzes phosphodiester bond formation at DNA nicks with 3' hydroxyl and 5' phosphate termini. Three human genes encode ATP-dependent DNA ligases. These enzymes have a conserved catalytic core consisting of three subdomains that encircle nicked duplex DNA during ligation. The DNA ligases are targeted to different nuclear DNA transactions by specific protein-protein interactions. Both DNA ligase IIIα and DNA ligase IV form stable complexes with DNA repair proteins, XRCC1 and XRCC4, respectively. There is functional redundancy between DNA ligase I and DNA ligase IIIα in DNA replication, excision repair and single-strand break repair. Although DNA ligase IV is a core component of the major double-strand break repair pathway, non-homologous end joining, the other enzymes participate in minor, alternative double-strand break repair pathways. In contrast to the nucleus, only DNA ligase IIIα is present in mitochondria and is essential for maintaining the mitochondrial genome. Human immunodeficiency syndromes caused by mutations in either LIG1 or LIG4 have been described. Preclinical studies with DNA ligase inhibitors have identified potentially targetable abnormalities in cancer cells and evidence that DNA ligases are potential targets for cancer therapy.Copyright © 2023 Elsevier Ltd. All rights reserved.