Turnover of BRCA1 involves in radiation-induced apoptosis.
Turnover of BRCA1 involves in radiation-induced apoptosis.
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DOI：
10.1371/journal.pone.0014484
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发表时间：
2010-12-31
期刊：
影响因子：
3.7
通讯作者：
Wan Y
中科院分区：
文献类型：
--
作者：
Liu W;Zong W;Wu G;Fujita T;Li W;Wu J;Wan Y
乳腺癌易感基因-1 （BRCA1）的种系突变增加了肿瘤发生的易感性。BRCA1的功能是调节关键的细胞过程，包括细胞周期进程、基因组完整性和凋亡。对BRCA1调控的研究主要集中在转录和磷酸化机制上。BRCA1蛋白水解调控对应激信号的响应在很大程度上仍然未知。该手稿确定了一种新的机制，通过该机制，BRCA1受泛素依赖性降解的调控，以响应电离。在这里，我们报道了严重的电离触发BRCA1的快速降解，这反过来导致细胞凋亡的激活。电离诱导的BRCA1转换是通过泛素-蛋白酶体途径介导的。BRCA1的稳定显著延缓了电离诱导的细胞凋亡的发生。我们已经绘制了BRCA1上的基本区域，该区域在电离反应中介导其蛋白水解。此外，我们已经证明BRCA1蛋白在G2/M期和S期电离时对降解最敏感。我们的研究结果表明，泛素蛋白酶体在基因毒性应激中调控BRCA1发挥重要作用。BRCA1蛋白水解调控参与电离诱导的细胞凋亡。
Germ-line mutations of the breast cancer susceptibility gene-1 (BRCA1) increase the susceptibility to tumorigenesis. The function of BRCA1 is to regulate critical cellular processes, including cell cycle progression, genomic integrity, and apoptosis. Studies on the regulation of BRCA1 have focused intensely on transcription and phosphorylation mechanisms. Proteolytic regulation of BRCA1 in response to stress signaling remains largely unknown. The manuscript identified a novel mechanism by which BRCA1 is regulated by the ubiquitin-dependent degradation in response to ionization. Here, we report that severe ionization triggers rapid degradation of BRCA1, which in turn results in the activation of apoptosis. Ionization-induced BRCA1 turnover is mediated via an ubiquitin-proteasomal pathway. The stabilization of BRCA1 significantly delays the onset of ionization-induced apoptosis. We have mapped the essential region on BRCA1, which mediates its proteolysis in response to ionization. Moreover, we have demonstrated that BRCA1 protein is most sensitive to degradation when ionization occurs during G2/M and S phase. Our results suggest that ubiquitin-proteasome plays an important role in regulating BRCA1 during genotoxic stress. Proteolytic regulation of BRCA1 involves in ionization-induced apoptosis.
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影响因子：
56.9
作者：
FUTREAL, PA;LIU, QY;WISEMAN, R
通讯作者：
WISEMAN, R
影响因子：
56.9
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作者：
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通讯作者：
Boulton, Simon J.