Brca2 (XRCC11) deficiency results in radioresistant DNA synthesis and a higher frequency of spontaneous deletions
Brca2 (XRCC11) deficiency results in radioresistant DNA synthesis and a higher frequency of spontaneous deletions
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DOI：
10.1128/mcb.22.2.669-679.2002
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发表时间：
2002-01-01
影响因子：
5.3
通讯作者：
Zdzienicka, MZ
中科院分区：
文献类型：
--
作者：
Kraakman-van der Zwet, M;Overkamp, WJI;Zdzienicka, MZ
我们在这里表明，放射敏感的中国仓鼠细胞突变体（V-C8）组XRCC 11是有缺陷的乳腺癌易感基因Brca 2。V-C8细胞的非常复杂的表型由提供BRCA 2基因的单个人13号染色体以及鼠Brca 2基因补充。V-C8细胞中的Brca 2缺陷引起对各种DNA损伤剂的超敏反应，对链间DNA交联剂具有极端敏感性。此外，V-C8细胞在电离辐射后显示出辐射抗性DNA合成，表明Brca 2缺乏影响细胞周期检查点调控。此外，V-C8细胞显示出巨大的染色体不稳定性和异常中心体的高频率。hprt基因座的突变谱显示，与野生型V79细胞相比，V-C8细胞中的大多数自发突变是缺失。Brca 2缺陷细胞的基因组不稳定表型的机制解释是通过观察到同源重组中的中央DNA修复蛋白Rad 51的核定位在V-C8细胞中减少而提供的。
We show here that the radiosensitive Chinese hamster cell mutant (V-C8) of group XRCC11 is defective in the breast cancer susceptibility gene Brca2. The very complex phenotype of V-C8 cells is complemented by a single human chromosome 13 providing the BRCA2 gene, as well as by the murine Brca2 gene. The Brca2 deficiency in V-C8 cells causes hypersensitivity to various DNA-damaging agents with an extreme sensitivity toward interstrand DNA cross-linking agents. Furthermore, V-C8 cells show radioresistant DNA synthesis after ionizing radiation, suggesting that Brca2 deficiency affects cell cycle checkpoint regulation. In addition, V-C8 cells display tremendous chromosomal instability and a high frequency of abnormal centrosomes. The mutation spectrum at the hprt locus showed that the majority of spontaneous mutations in V-C8 cells are deletions, in contrast to wild-type V79 cells. A mechanistic explanation for the genome instability phenotype of Brca2-deficient cells is provided by the observation that the nuclear localization of the central DNA repair protein in homologous recombination, Rad51, is reduced in V-C8 cells.