The BRCA1/BARD1 heterodimer modulates ran-dependent mitotic spindle assembly
The BRCA1/BARD1 heterodimer modulates ran-dependent mitotic spindle assembly
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DOI：
10.1016/j.cell.2006.08.053
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发表时间：
2006-11-03
期刊：
影响因子：
64.5
通讯作者：
Livingston, David M.
中科院分区：
文献类型：
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作者：
Joukov, Vladimir;Groen, Aaron C.;Livingston, David M.
异源二聚体肿瘤抑制复合物BRCA 1/BARD 1具有E3泛素连接酶活性，并通过不完全确定的机制参与细胞增殖和染色体稳定性控制。在这里，我们表明，在哺乳动物细胞和非洲爪蟾卵提取物，BRCA 1/BARD 1所需的有丝分裂纺锤体极组装和积累的TPX 2，一个主要的纺锤体组织者和RAN目标，纺锤体极。该功能是中心体独立的，在Ran GT3下游起作用，并且依赖于BRCA 1/BARD 1 E3泛素连接酶活性。非洲爪蟾BRCA 1/BARD 1与三种纺锤极蛋白TPX 2、NuMA和XRHAMM（一种已知的TPX 2伴侣）形成内源性复合物，并特异性地减弱XRHAMM功能。这些观察结果揭示了BRCA 1/BARD 1在有丝分裂纺锤体组装中以前未被认识的功能，这可能有助于其在染色体稳定性控制和肿瘤抑制中的作用。
The heterodimeric tumor-suppressor complex BRCA1/BARD1 exhibits E3 ubiquitin ligase activity and participates in cell proliferation and chromosome stability control by incompletely defined mechanisms. Here we show that, in both mammalian cells and Xenopus egg extracts, BRCA1/BARD1 is required for mitotic spindle-pole assembly and for accumulation of TPX2, a major spindle organizer and Ran target, on spindle poles. This function is centrosome independent, operates downstream of Ran GTPase, and depends upon BRCA1/BARD1 E3 ubiquitin ligase activity. Xenopus BRCA1/BARD1 forms endogenous complexes with three spindle-pole proteins, TPX2, NuMA, and XRHAMM-a known TPX2 partner-and specifically attenuates XRHAMM function. These observations reveal a previously unrecognized function of BRCA1/BARD1 in mitotic spindle assembly that likely contributes to its role in chromosome stability control and tumor suppression.