Akt1 inhibits homologous recombination in Brca1-deficient cells by blocking the Chk1-Rad51 pathway.
Akt1 inhibits homologous recombination in Brca1-deficient cells by blocking the Chk1-Rad51 pathway.
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DOI：
10.1038/onc.2012.211
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发表时间：
2013-04-11
期刊：
影响因子：
8
通讯作者：
Yang, Q.
中科院分区：
文献类型：
--
作者：
Jia, Y.;Song, W.;Zhang, F.;Yan, J.;Yang, Q.
BRCA1缺乏会导致乳腺癌的发生。我们先前发现BRCA1缺乏激活Akt致癌途径。乳腺癌标本中BRCA1表达降低与Akt活性升高高度相关。此外，Akt1的激活参与了BRCA1缺陷介导的小鼠肿瘤的发生。有缺陷的同源重组(HR)被认为是BRCA1缺乏症肿瘤发生的主要因素。在这里，我们表明Akt1促进了BRCA1缺陷细胞的染色体不稳定性。BRCA1缺陷细胞中的DNA断裂通过依赖Akt1的过程异常地连接到复杂的染色体重排中。缺失Akt1会增加BRCA1突变细胞的心率，野生型的表达可以拯救BRCA1突变细胞，但缺失BRCA1结合结构域的突变Akt1不会增加HR。在机制上，BRCA1缺陷细胞中Akt1的激活会损害Chk1的核定位，进而破坏Chk1和RAD51的相互作用，导致HR缺陷。我们的结果表明BRCA1缺乏可能通过调节Chk1-RAD51信号而激活Akt1，从而促进肿瘤的发生。
Brca1 deficiency leads to the development of breast cancer. We previously found that Brca1 deficiency activates the Akt oncogenic pathway. Reduced expression of Brca1 was highly correlated with increased activated Akt in human breast cancer samples. Furthermore, activation of Akt1 was involved in Brca1-deficiency-mediated tumorigenesis in mice. Defective homologous recombination (HR) is thought to be a major contributor to tumorigenesis in Brca1 deficiency. Here, we show that Akt1 promotes chromosome instability in Brca1-deficent cells. DNA breaks in Brca1-deficent cells are aberrantly joined into complex chromosome rearrangements by a process dependent on Akt1. Depletion of Akt1 increases HR in Brca1-mutant cells, which is rescued by expression of wild-type, but not mutant Akt1 with deletion of Brca1-binding domain. Mechanistically, activated Akt1 in Brca1-deficient cells impairs Chk1 nuclear localization and subsequently disrupts interaction of Chk1 and Rad51 leading to HR defects. Our results indicate that Brca1 deficiency might activate Akt1 contributing to tumorigenesis through regulation of the Chk1-Rad51 signaling.
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