The joining of interruptions in the phosphodiester backbone of DNA is critical to maintain genome stability. These breaks, which are generated as part of normal DNA transactions, such as DNA replication, V(D)J recombination and meiotic recombination as well as directly by DNA damage or due to DNA damage removal, are ultimately sealed by one of three human DNA ligases. DNA ligases I, III and IV each function in the nucleus whereas DNA ligase III is the sole enzyme in mitochondria. While the identification of specific protein partners and the phenotypes caused either by genetic or chemical inactivation have provided insights into the cellular functions of the DNA ligases and evidence for significant functional overlap in nuclear DNA replication and repair, different results have been obtained with mouse and human cells, indicating species-specific differences in the relative contributions of the DNA ligases. Inherited mutations in the human LIG1 and LIG4 genes that result in the generation of polypeptides with partial activity have been identified as the causative factors in rare DNA ligase deficiency syndromes that share a common clinical symptom, immunodeficiency. In the case of DNA ligase IV, the immunodeficiency is due to a defect in V(D)J recombination whereas the cause of the immunodeficiency due to DNA ligase I deficiency is not known. Overexpression of each of the DNA ligases has been observed in cancers. For DNA ligase I, this reflects increased proliferation. Elevated levels of DNA ligase III indicate an increased dependence on an alternative non-homologous end-joining pathway for the repair of DNA double-strand breaks whereas elevated level of DNA ligase IV confer radioresistance due to increased repair of DNA double-strand breaks by the major non-homologous end-joining pathway. Efforts to determine the potential of DNA ligase inhibitors as cancer therapeutics are on-going in preclinical cancer models.

中文翻译：

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改变人类疾病中的 DNA 连接酶活性。

DNA 磷酸二酯骨架中中断的连接对于维持基因组稳定性至关重要。这些断裂是作为正常 DNA 交易的一部分产生的，例如 DNA 复制、V(D)J 重组和减数分裂重组，以及直接由 DNA 损伤或由于 DNA 损伤去除，最终由三种人类 DNA 之一密封连接酶。DNA 连接酶 I、III 和 IV 均在细胞核中起作用，而 DNA 连接酶 III 是线粒体中唯一的酶。虽然特定蛋白质伴侣和由遗传或化学失活引起的表型的鉴定提供了对 DNA 连接酶的细胞功能的洞察以及核 DNA 复制和修复中显着功能重叠的证据，但在小鼠和人类身上获得了不同的结果。细胞，表明 DNA 连接酶的相对贡献的物种特异性差异。导致产生具有部分活性的多肽的人类 LIG1 和 LIG4 基因中的遗传突变已被确定为罕见 DNA 连接酶缺陷综合征的致病因素，这些综合征具有共同的临床症状，即免疫缺陷。在 DNA 连接酶 IV 的情况下，免疫缺陷是由于 V(D)J 重组缺陷，而由于 DNA 连接酶 I 缺陷引起的免疫缺陷的原因尚不清楚。已在癌症中观察到每种 DNA 连接酶的过度表达。对于 DNA 连接酶 I，这反映了增殖的增加。DNA 连接酶 III 水平升高表明对 DNA 双链断裂修复的替代非同源末端连接途径的依赖性增加，而 DNA 连接酶 IV 水平升高由于 DNA 双链断裂修复增加而赋予放射抗性主要的非同源末端连接途径。在临床前癌症模型中，正在努力确定 DNA 连接酶抑制剂作为癌症治疗剂的潜力。