O'Driscoll M, Cerosaletti K M, Girard P M, Dai Y, Stumm M, Kysela B, Hirsch B, Gennery A, Palmer S E, Seidel J, Gatti R A, Varon R, Oettinger M A, Neitzel H, Jeggo P A, Concannon P
Genome Damage and Stability Unit, University of Sussex, Brighton, East Sussex, BN1 9RR, United Kingdom.
Mol Cell. 2001 Dec;8(6):1175-85. doi: 10.1016/s1097-2765(01)00408-7.
DNA ligase IV functions in DNA nonhomologous end-joining and V(D)J recombination. Four patients with features including immunodeficiency and developmental and growth delay were found to have mutations in the gene encoding DNA ligase IV (LIG4). Their clinical phenotype closely resembles the DNA damage response disorder, Nijmegen breakage syndrome (NBS). Some of the mutations identified in the patients directly disrupt the ligase domain while others impair the interaction between DNA ligase IV and Xrcc-4. Cell lines from the patients show pronounced radiosensitivity. Unlike NBS cell lines, they show normal cell cycle checkpoint responses but impaired DNA double-strand break rejoining. An unexpected V(D)J recombination phenotype is observed involving a small decrease in rejoining frequency coupled with elevated imprecision at signal junctions.
DNA连接酶IV在DNA非同源末端连接和V(D)J重组中发挥作用。发现四名具有免疫缺陷、发育和生长迟缓等特征的患者在编码DNA连接酶IV（LIG4）的基因中存在突变。他们的临床表型与DNA损伤反应障碍尼曼-匹克氏综合征（NBS）极为相似。在患者中鉴定出的一些突变直接破坏了连接酶结构域，而其他突变则损害了DNA连接酶IV与Xrcc-4之间的相互作用。患者的细胞系表现出明显的放射敏感性。与NBS细胞系不同，它们显示出正常的细胞周期检查点反应，但DNA双链断裂重新连接受损。观察到一种意外的V(D)J重组表型，包括重新连接频率略有下降以及信号接头处的不精确性升高。
