The nonhomologous end-joining pathway of DNA repair is required for genomic stability and the suppression of translocations
The nonhomologous end-joining pathway of DNA repair is required for genomic stability and the suppression of translocations
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DOI：
10.1073/pnas.110152897
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发表时间：
2000-06-06
影响因子：
11.1
通讯作者：
Alt, FW
中科院分区：
文献类型：
--
作者：
Ferguson, DO;Sekiguchi, JM;Alt, FW
我们使用光谱核型分析来评估非同源 DNA 末端连接途径的三种不同成分在维持小鼠胚胎成纤维细胞 (MEF) 基因组稳定性中的潜在作用，对于使 DNA 连接酶 IV (Lig4) 或 Ku70 失活的突变纯合的 MEF，即使在没有外源 DNA 的情况下也表现出显着的基因组不稳定性。 破坏剂。这些异常事件的范围从染色体断裂到可能涉及多个染色体的非相互易位。 DNA 依赖性蛋白激酶催化亚基缺陷也会促进基因组不稳定。 p53 细胞周期检查点蛋白的缺乏对 Lig4 缺陷的成纤维细胞自发的染色体不稳定性水平影响不大。然而，在电离辐射治疗的背景下，p53 缺陷使得 Lig4 缺陷 MEF 中出现大规模急性染色体破坏，在存活细胞中表现为频繁的非互易易位。我们得出结论，非同源 DNA 末端连接作为哺乳动物基因组的看护者发挥着至关重要的作用，并且存在一种替代修复途径，通常会导致 到非互易易位。
We have used spectral karyotyping to assess potential roles of three different components of the nonhomologous DNA end-joining pathway in the maintenance of genomic stability in mouse embryonic fibroblasts (MEFs), MEFs homozygous for mutations that inactivate either DNA ligase IV (Lig4) or Ku70 display dramatic genomic instability, even in the absence of exogenous DNA damaging agents. These aberrant events range from chromosomal fragmentation to nonreciprocal translocations that can involve several chromosomes. DNA-dependent protein kinase catalytic subunit deficiency also promotes genome instability. Deficiency for the p53 cell cycle checkpoint protein has little effect on spontaneous levels of chromosomal instability in Lig4-deficient fibroblasts. However, in the context of ionizing radiation treatment, p53 deficiency allowed visualization of massive acute chromosomal destruction in Lig4-deficient MEFs, which in surviving cells manifested as frequent nonreciprocal translocations, We conclude that nonhomologous DNA end-joining plays a crucial role as a caretaker of the mammalian genome, and that an alternative repair pathway exists that often leads to nonreciprocal translocations.