Recent studies have revealed a structural role for DNA ligase 4 (Lig4) in the maintenance of a repair complex during non-homologous end joining (NHEJ) of DNA double-strand breaks. In cultured cell lines, catalytically inactive Lig4 can partially alleviate the severe DNA repair phenotypes observed in cells lacking Lig4. To study the structural role of Lig4 in vivo, a mouse strain harboring a point mutation to Lig4’s catalytic site was generated. In contrast to the ablation of Lig4, catalytically inactive Lig4 mice are born alive. These mice display marked growth retardation and have clear deficits in lymphocyte development. We considered that the milder phenotype results from inactive Lig4 help to recruit another ligase to the repair complex. We next generated a mouse strain deficient for nuclear Lig3. Nuclear Lig3-deficient mice are moderately smaller and have elevated incidences of cerebral ventricle dilation but otherwise appear normal. Strikingly, in experiments crossing these two strains, mice lacking nuclear Lig3 and expressing inactive Lig4 were not obtained. Timed mating revealed that fetuses harboring both mutations underwent resorption, establishing an embryonic lethal genetic interaction. These data suggest that Lig3 is recruited to NHEJ complexes to facilitate end joining in the presence (but not activity) of Lig4.

中文翻译：

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通过催化失活的 Lig4 对小鼠活力和 DNA 双链断裂修复的 Lig3 依赖性拯救


最近的研究表明，DNA 连接酶 4 （Lig4） 在 DNA 双链断裂的非同源末端连接 （NHEJ） 期间维持修复复合物的结构作用。在培养的细胞系中，催化失活的 Lig4 可以部分缓解在缺乏 Lig4 的细胞中观察到的严重 DNA 修复表型。为了研究 Lig4 在体内的结构作用，产生了一种对 Lig4 催化位点携带点突变的小鼠品系。与 Lig4 的消融相反，催化失活的 Lig4 小鼠出生时是活的。这些小鼠表现出明显的生长迟缓，并且在淋巴细胞发育方面有明显的缺陷。我们认为失活的 Lig4 导致的较温和的表型有助于将另一种连接酶募集到修复复合物中。接下来，我们生成了缺乏核 Lig3 的小鼠品系。核 Lig3 缺陷小鼠体型适中，脑室扩张的发生率升高，但其他方面看起来正常。引人注目的是，在杂交这两种菌株的实验中，没有获得缺乏核 Lig3 和表达无活性 Lig4 的小鼠。定时交配显示，携带这两种突变的胎儿都发生了吸收，建立了胚胎致命的遗传相互作用。这些数据表明，Lig3 被募集到 NHEJ 复合物中，以促进在 Lig4 存在（但不是活性）的情况下结束连接。