In mammalian cells, the process of DNA ligation is necessary during DNA replication to create an intact “lagging” strand from a series of smaller Okazaki fragments and to repair DNA strand breaks that arise either due to the direct action of a DNA damaging agent or as a consequence of DNA damage excision during DNA repair. In humans, there are three genes that encode for members of the DNA ligase family (LIG1, LIG3 and LIG4) (Ellenberger and Tomkinson in Ann Rev Biochem 77:313–338. 2008). Although these genes code for polypeptides with overlapping functions in the nucleus, the only mitochondrial DNA ligase (DNA ligase IIIα), which is essential for mitochondrial genome maintenance, is encoded by the LIG3 gene (Lakshmipathy and Campbell in Mol Cell Biol 19:3869–3876, 1999; Zong et al. in Mol Cell 61:667–676, 2016) Because mitochondria play a central and multifunctional role in malignant tumor progression, there is emerging interest in targeting key mitochondrial proteins. Notably, there is evidence in pre-clinical models that inhibitors of DNA ligase IIIα, which is frequently up-regulated in cancer, preferentially target cancer cells via their effect on mitochondria (Zong et al. 2016). Since NMR spectroscopy provides unique capabilities for identifying small molecules that bind specifically to DNA ligase IIIα versus the other DNA ligases), the backbone ¹H^N, ¹³C, and ¹⁵N NMR resonance assignments were completed for a 222 amino acid DNA-binding domain of human DNA ligase III. These NMR assignments represent a vital first step towards developing DNA ligase III-selective inhibitors.

中文翻译：

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人DNA连接酶3 DNA结合域的1HN，13C和15N骨架共振分配（残基257-477）。

在哺乳动物细胞中，DNA复制过程中必须进行DNA连接过程，以从一系列较小的Okazaki片段中形成完整的“滞后”链，并修复由于DNA破坏剂的直接作用或DNA断裂而产生的DNA链断裂。 DNA修复过程中DNA损伤切除的后果。在人类中，存在三个编码DNA连接酶家族成员的基因（LIG1，LIG3和LIG4）（Ellenberger和Tomkinson，Ann Rev Biochem 77：313–338。2008）。尽管这些基因编码在核中具有重叠功能的多肽，但是唯一的线粒体DNA连接酶（DNA连接酶IIIα）是线粒体基因组维持所必需的，由LIG3编码基因（Lakshmipathy和Campbell在Mol Cell Biol 19：3869–3876，1999; Zong等人在Mol Cell 61：667–676，2016）中。由于线粒体在恶性肿瘤进展中起着核心和多功能的作用，因此人们越来越关注靶向关键的线粒体蛋白。值得注意的是，在临床前模型中有证据表明，DNA连接酶IIIα的抑制剂（通常在癌症中上调）通过其对线粒体的作用优先靶向癌细胞（Zong等人，2016）。由于NMR光谱法提供了独特的能力来鉴定与其他DNA连接酶特异性结合的与DNA连接酶IIIα结合的小分子，因此骨架¹ H ^N，¹³ C和¹⁵对人DNA连接酶III的222个氨基酸的DNA结合结构域完成了N NMR共振分配。这些NMR代表了开发DNA连接酶III选择性抑制剂的至关重要的第一步。