HERC2 Is an E3 Ligase That Targets BRCA1 for Degradation
HERC2 Is an E3 Ligase That Targets BRCA1 for Degradation
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DOI：
10.1158/0008-5472.can-10-1304
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发表时间：
2010-08-01
期刊：
影响因子：
11.2
通讯作者：
Ohta, Tomohiko
中科院分区：
文献类型：
--
作者：
Wu, Wenwen;Sato, Ko;Ohta, Tomohiko
乳腺癌抑制基因BRCA1与BARD1形成稳定的异二聚体E3泛素连接酶。每种蛋白质控制着另一种蛋白质的丰度和稳定性，相互作用的丧失会导致BRCA1的降解。在这里，我们证明了HERC2，一个最近参与DNA损伤修复的蛋白质，目标是BARD1解偶联的BRCA1进行降解。HERC2穿梭于细胞核和细胞质之间。它的COOH末端的Hect结构域与BRCA1中的NH2末端的degron结构域相互作用。HERC2泛素化BRCA1；该反应依赖于HERC2的Cys(4762)、催化的泛素结合部位和BRCA1的降解。HERC2-BRCA1的相互作用在细胞周期的S期达到最大，并随着细胞进入G(2)-M期而迅速减弱，与BRCA1的稳态水平呈负相关。值得注意的是，HERC2缺失通过恢复BRCA1表达和G(2)-M检查点活性来拮抗BARD1缺失的影响。相反，BARD1保护BRCA1免受HERC2介导的泛素化。总体而言，我们的发现确定了HERC2在调节BRCA1稳定性方面的功能，而不是BARD1。HERC2在乳腺上皮细胞和乳腺癌中的表达提示该机制可能在乳腺癌的发生发展中起一定作用。癌症资源；70(15)；6384-92。(C)2010年AACR。
The breast cancer suppressor BRCA1 forms a stable heterodimeric E3 ubiquitin ligase with BARD1. Each protein controls the abundance and stability of the other, and loss of the interaction leads to BRCA1 degradation. Here, we show that HERC2, a protein recently implicated in DNA damage repair, targets BARD1-uncoupled BRCA1 for degradation. HERC2 shuttles between the nucleus and the cytoplasm. Its COOH-terminal HECT-containing domain interacts with an NH2-terminal degron domain in BRCA1. HERC2 ubiquitinates BRCA1; this reaction depends on Cys(4762) of HERC2, the catalytic ubiquitin binding site, and the degron of BRCA1. The HERC2-BRCA1 interaction is maximal during the S phase of the cell cycle and rapidly diminishes as cells enter G(2)-M, inversely correlated with the steady-state level of BRCA1. Significantly, HERC2 depletion antagonizes the effects of BARD1 depletion by restoring BRCA1 expression and G(2)-M checkpoint activity. Conversely, BARD1 protects BRCA1 from HERC2-mediated ubiquitination. Collectively, our findings identify a function for HERC2 in regulating BRCA1 stability in opposition to BARD1. The HERC2 expression in breast epithelial cells and breast carcinomas suggests that this mechanism may play a role in breast carcinogenesis. Cancer Res; 70(15); 6384-92. (C) 2010 AACR.