Distinct Roles of BARD1 Isoforms in Mitosis: Full-Length BARD1 Mediates Aurora B Degradation, Cancer-Associated BARD1β Scaffolds Aurora B and BRCA2
Distinct Roles of BARD1 Isoforms in Mitosis: Full-Length BARD1 Mediates Aurora B Degradation, Cancer-Associated BARD1β Scaffolds Aurora B and BRCA2
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DOI：
10.1158/0008-5472.can-08-2134
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发表时间：
2009-02-01
期刊：
影响因子：
11.2
通讯作者：
Irminger-Finger, Irmgard
中科院分区：
文献类型：
--
作者：
Ryser, Stephan;Dizin, Eva;Irminger-Finger, Irmgard
BRCA1相关环域蛋白1(BARD1)通过其环指结构域与BRCA1相互作用。BARD1-BRCA1复合体通过其E3泛素连接酶活性参与DNA修复、细胞周期控制、基因组稳定性和有丝分裂纺锤体的形成。癌细胞表达几种BARD1蛋白亚型，包括缺乏无名指的BARD1beta。在这里，我们证明了BARD1在有丝分裂中具有BRCA1依赖和BRCA1不依赖的功能。BARD1，而不是BRCA1，在末期和胞质分裂时定位于中体，在那里它与Aurora B共存。97 kDa全长(FL)BARD1与BRCA1共沉淀，而82 kDa BARD1β与Aurora B和BRCA2共沉淀。我们使用选择性小干扰RNA来区分FL BARD 1和BARD 1β的功能。缺失FL BARD1对细胞生长的影响很小，并没有取消BARD1染色的中体定位，但导致Aurora B的大量上调。相反，抑制FL BARD1和BARD1β导致生长停滞，并与各种有丝分裂缺陷和BARD1染色中体定位的消失有关。我们的数据表明，FL BARD1在Aurora B泛素化和降解中具有新的功能，与BARD1β在支架Aurora B和BRCA2中的促增殖功能相反。因此，在癌细胞中观察到的FL BARD1的丢失和Aurora B的上调可以用FL BARD1和BARD1β的失衡来解释。[癌症资源2009；69(3)：1125-34]
The BRCA1-associated ring domain protein 1 (BARD1) interacts with BRCA1 via its RING finger domain. The BARD1-BRCA1 complex participates in DNA repair, cell cycle control, genomic stability, and mitotic spindle formation through its E3 ubiquitin ligase activity. Cancer cells express several BARD1 protein isoforms, including the RING finger-deficient variant BARD1 beta. Here, we show that BARD1 has BRCA1-dependent and BRCA1-independent functions in mitosis. BARD1, but not BRCA1, localizes to the midbody at telophase and cytokinesis, where it colocalizes with Aurora B. The 97-kDa full-length (FL) BARD1 coimmunoprecipates with BRCA1, but the 82-kDa BARD1 beta coimmunoprecipitates with Aurora B and BRCA2. We used selective small interfering RNAs to distinguish the functions of FL BARD1 and BARD1 beta. Depletion of FL BARD1 had only minor effects on cell growth and did not abolish midbody localization of BARD1 staining, but resulted in massive up-regulation of Aurora B. In contrast, suppression of FL BARD1 and BARD1 beta led to growth arrest and correlated with various mitotic defects and disappearance of midbody localization of BARD1 staining. Our data suggest a novel function of FL BARD1 in Aurora B ubiquitination and degradation, opposing a proproliferative function of BARD1 beta in scaffolding Aurora B and BRCA2. Thus, loss of FL BARD1 and up-regulation of Aurora B, as observed in cancer cells, can be explained by an imbalance of FL BARD1 and BARD1 beta. [Cancer Res 2009;69(3):1125-34]