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首页> 外文期刊>International Journal of Radiation Biology: Covering the Physical, Chemical, Biological, and Medical Effects of Ionizing and Non-ionizing Radiations >Differing effects of breast cancer 1, early onset (BRCA1) and ataxia-telangiectasia mutated (ATM) mutations on cellular responses to ionizing radiation.
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Differing effects of breast cancer 1, early onset (BRCA1) and ataxia-telangiectasia mutated (ATM) mutations on cellular responses to ionizing radiation.

机译：乳腺癌1，早发（BRCA1）和共济失调毛细血管扩张突变（ATM）突变对细胞对电离辐射的反应的不同影响。

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PURPOSE: The ataxia-telangiectasia mutated (ATM) gene encodes a protein kinase, the activation of which is an early event in the cellular response to ionizing radiation. One of the many substrates of ATM is BRCA1 (breast cancer 1, early onset gene), which has been associated with susceptibility to breast and ovarian cancer, and has been implicated in DNA repair processes. Various cellular responses to radiation were analysed in cells with mutations in ATM or BRCA1 in an attempt to clarify which effects of ATM can be mediated through BRCA1. MATERIALS AND METHODS: The response to radiation of cells with mutations in ATM or BRCA1 was examined, as were BRCA1-mutant tumour cells transfected with an exogenous wild-type BRCA1 allele. Assays included cell-survival curves, studies of potentially lethal damage repair, measurement of chromosomal aberrations and of G1 arrest, and Western blot analysis of lysates of irradiated cells to determine the phosphorylation of the product of the human Mdm2 gene (HDM2). RESULTS: Both ATM and BRCA1 mutations were associated with sensitivity to ionizing radiation, deficient repair of potentially lethal damage and markedly increased chromosomal aberrations. A BRCA1-mutated tumour cell line HCC1937, like ATM mutant cells, did not exhibit a normal G1 arrest but, unlike ATM mutant cells, did exhibit phosphorylation of HDM2. Expression of wild-type BRCA1 in HCC1937 cells partially restored radioresistance, restored repair of potentially lethal damage and markedly reduced radiation-induced chromosomal aberrations. G1 arrest, however, was not restored by expression of BRCA1. CONCLUSIONS: The results are consistent with a model in which ATM phosphorylation of BRCA1 regulates DNA repair functions, particularly those involved in potentially lethal damage repair and chromosomal integrity, but not other aspects of the cellular response to radiation such as G1 cell cycle arrest. To the authors' knowledge, this is the first demonstration of the ability of exogenously expressed BRCA1 to restore the ability to perform potentially lethal damage repair and maintain chromosomal integrity in irradiated cells.
机译：目的：共济失调-毛细血管扩张突变（ATM）基因编码一种蛋白激酶，其激活是细胞对电离辐射的早期反应。 ATM的许多底物之一是BRCA1（乳腺癌1，早期发病基因），它与乳腺癌和卵巢癌的易感性有关，并且与DNA修复过程有关。分析了ATM或BRCA1突变的细胞对辐射的各种细胞反应，以试图阐明可以通过BRCA1介导哪些ATM效应。材料与方法：检查了ATM或BRCA1中突变的细胞对辐射的反应，以及用外源野生型BRCA1等位基因转染的BRCA1突变肿瘤细胞。分析包括细胞存活曲线，潜在致死性损伤修复研究，染色体畸变和G1阻滞的测量以及辐照细胞裂解物的蛋白质印迹分析，以确定人类Mdm2基因（HDM2）产物的磷酸化。结果：ATM和BRCA1突变均与对电离辐射的敏感性，潜在致死性损伤的修复不足以及染色体畸变显着相关。像ATM突变细胞一样，BRCA1突变的肿瘤细胞系HCC1937没有显示正常的G1阻滞，但是与ATM突变细胞不同，它确实显示了HDM2的磷酸化。 HCC1937细胞中野生型BRCA1的表达部分恢复了抗辐射性，恢复了可能致命的破坏的修复，并显着降低了辐射诱导的染色体畸变。但是，G1逮捕并未通过表达BRCA1恢复。结论：该结果与BRCA1的ATM磷酸化调节DNA修复功能的模型相符，特别是那些涉及潜在致死性损伤修复和染色体完整性的DNA修复功能，而不是细胞对辐射的其他反应例如G1细胞周期停滞的其他方面。据作者所知，这是外源表达的BRCA1恢复被照射细胞中执行潜在致命性损伤修复和维持染色体完整性的能力的第一个证明。

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