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Cell cycle and genetic background dependence of the effect of loss of BRCA2 on ionizing radiation sensitivity

机译：BRCA2丢失对电离辐射敏感性影响的细胞周期和遗传背景依赖性

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摘要

Carriers of mutations in the BRCA2 gene are at a highly elevated risk of breast and other cancers. The BRCA2 gene encodes a very large protein thought to play a role in DNA repair. To examine the effect of mutation of BRCA2 on sensitivity to ionizing radiation, we used a previously described mouse model system (Brca2Tr) in which the Brca2 open reading frame is truncated. Mouse embryo fibroblasts carrying this mutation have a proliferative defect, which we show here can be substantially rescued by genetic ablation of p53. Proliferating Brca2Tr/Tr/p53-/- cells, like Brca2Tr/Tr cells, show genomic instability. We used the clonogenic survival assay, which depends on the ability of cells to proliferate, to examine the cell cycle dependence of radiation sensitivity of Brca2Tr/Tr/p53-/- compared to p53-/- and wild-type cells. This showed that the Brca2 mutation had little effect on cells irradiated in quiescence but sensitized proliferating cells to ionizing radiation on a p53-/- background. These results suggest that the major role of Brca2 in mediating cell survival after irradiation is in the S and G2 phases of the cell cycle.
机译：BRCA2基因突变的携带者患乳腺癌和其他癌症的风险很高。 BRCA2基因编码一种非常大的蛋白质，被认为在DNA修复中起作用。若要检查BRCA2突变对电离辐射敏感性的影响，我们使用了先前描述的小鼠模型系统（Brca2Tr），其中Brca2开放阅读框被截断了。携带该突变的小鼠胚胎成纤维细胞具有增生缺陷，我们在这里表明可以通过基因切除p53基本上挽救该缺陷。像Brca2Tr / Tr细胞一样，增殖的Brca2Tr / Tr / p53-/-细胞显示出基因组不稳定。我们根据细胞增殖的能力使用克隆形成存活测定法来检查Brca2Tr / Tr / p53-/-与p53-/-和野生型细胞辐射敏感性的细胞周期依赖性。这表明Brca2突变对静止辐射的细胞几乎没有影响，但是使增殖细胞对p53-/-背景下的电离辐射敏感。这些结果表明，Brca2在辐射后介导细胞存活中的主要作用在于细胞周期的S和G2期。

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