Frank K M, Sekiguchi J M, Seidl K J, Swat W, Rathbun G A, Cheng H L, Davidson L, Kangaloo L, Alt F W
The Children's Hospital, Department of Genetics, Harvard University Medical School, Boston, Massachusetts 02115, USA.
Nature. 1998 Nov 12;396(6707):173-7. doi: 10.1038/24172.
The DNA-end-joining reactions used for repair of double-strand breaks in DNA and for V(D)J recombination, the process by which immunoglobulin and T-cell antigen-receptor genes are assembled from multiple gene segments, use common factors. These factors include components of DNA-dependent protein kinase (DNA-PK), namely DNA-PKcs and the Ku heterodimer, Ku70-Ku80, and XRCC4. The precise function of XRCC4 is unknown, but it interacts with DNA ligase IV. Ligase IV is one of the three known mammalian DNA ligases; however, the in vivo functions of these ligases have not been determined unequivocally. Here we show that inactivation of the ligase IV gene in mice leads to late embryonic lethality. Lymphopoiesis in these mice is blocked and V(D)J joining does not occur. Ligase IV-deficient embryonic fibroblasts also show marked sensitivity to ionizing radiation, growth defects and premature senescence. All of these phenotypic characteristics, except embryonic lethality, resemble those associated with Ku70 and Ku80 deficiencies, indicating that they may result from an impaired end-joining process that involves both Ku subunits and ligase IV. However, Ku-deficient mice are viable, so ligase IV must also be required for processes and/or in cell types in which Ku is dispensable.
用于修复DNA双链断裂以及V(D)J重组（免疫球蛋白和T细胞抗原受体基因由多个基因片段组装的过程）的DNA末端连接反应使用共同的因子。这些因子包括DNA依赖蛋白激酶（DNA-PK）的组分，即DNA-PKcs和Ku异二聚体Ku70-Ku80，以及XRCC4。XRCC4的确切功能尚不清楚，但它与DNA连接酶IV相互作用。连接酶IV是已知的三种哺乳动物DNA连接酶之一；然而，这些连接酶在体内的功能尚未明确确定。在这里，我们表明小鼠中连接酶IV基因的失活导致胚胎后期致死。这些小鼠的淋巴细胞生成受阻，V(D)J连接不发生。连接酶IV缺陷的胚胎成纤维细胞也对电离辐射表现出明显的敏感性、生长缺陷和过早衰老。除胚胎致死外，所有这些表型特征都类似于与Ku70和Ku80缺陷相关的特征，表明它们可能是由于涉及Ku亚基和连接酶IV的末端连接过程受损所致。然而，Ku缺陷的小鼠是存活的，因此在Ku可缺失的过程和/或细胞类型中，连接酶IV也必定是必需的。
