Gao Y, Sun Y, Frank K M, Dikkes P, Fujiwara Y, Seidl K J, Sekiguchi J M, Rathbun G A, Swat W, Wang J, Bronson R T, Malynn B A, Bryans M, Zhu C, Chaudhuri J, Davidson L, Ferrini R, Stamato T, Orkin S H, Greenberg M E, Alt F W
Howard Hughes Medical Institute, The Children's Hospital, Department of Genetics, Harvard University Medical School, Boston, Massachusetts 02115, USA.
Cell. 1998 Dec 23;95(7):891-902. doi: 10.1016/s0092-8674(00)81714-6.
XRCC4 was identified via a complementation cloning method that employed an ionizing radiation (IR)-sensitive hamster cell line. By gene-targeted mutation, we show that XRCC4 deficiency in primary murine cells causes growth defects, premature senescence, IR sensitivity, and inability to support V(D)J recombination. In mice, XRCC4 deficiency causes late embryonic lethality accompanied by defective lymphogenesis and defective neurogenesis manifested by extensive apoptotic death of newly generated postmitotic neuronal cells. We find similar neuronal developmental defects in embryos that lack DNA ligase IV, an XRCC4-associated protein. Our findings demonstrate that differentiating lymphocytes and neurons strictly require the XRCC4 and DNA ligase IV end-joining proteins and point to the general stage of neuronal development in which these proteins are necessary.
XRCC4是通过一种利用对电离辐射（IR）敏感的仓鼠细胞系的互补克隆方法鉴定出来的。通过基因靶向突变，我们发现原代鼠细胞中XRCC4的缺失会导致生长缺陷、早衰、对IR敏感以及无法支持V(D)J重组。在小鼠中，XRCC4的缺失会导致胚胎后期致死，并伴有有缺陷的淋巴细胞生成和神经发生缺陷，表现为新生成的有丝分裂后神经元细胞广泛凋亡死亡。我们在缺乏DNA连接酶IV（一种与XRCC4相关的蛋白质）的胚胎中发现了类似的神经元发育缺陷。我们的研究结果表明，分化中的淋巴细胞和神经元严格需要XRCC4和DNA连接酶IV末端连接蛋白，并指出了这些蛋白质发挥作用的神经元发育的一般阶段。
