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首页> 外文期刊>Oncogene >A CRM1-mediated nuclear export signal governs cytoplasmic localization of BRCA2 and is essential for centrosomal localization of BRCA2
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A CRM1-mediated nuclear export signal governs cytoplasmic localization of BRCA2 and is essential for centrosomal localization of BRCA2

机译：CRM1介导的核输出信号控制BRCA2的胞质定位，对于BRCA2的中心体定位必不可少

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Germ-line mutations of the BRCA2 gene cause inherited susceptibility to breast and ovarian cancers. BRCA2 contains two nuclear localization signals, predominantly localizes in the nucleus and plays significant roles in DNA double-strand break repair. Recently, we reported that BRCA2 localizes to the centrosomes during the S and early M phases of the cell cycle. In this study, for the first time, we identified a functional nuclear export sequence (NES1; 1383DLSDLTFLEVA1393) in BRCA2. The green fluorescent protein (GFP)-NES1 fusion protein was localized in the cytoplasm and could be blocked by the chromosomal region maintenance 1-specific export inhibitor leptomycin B. Mutation of a leucine residue in the NES1 motif to alanine (L1384A) resulted in both cytoplasmic and nuclear localization of the GFP-NES1 fusion protein and a nuclear accumulation of ectopic full-length BRCA2-FLAG. Moreover, treatment of cells with leptomycin B decreased centrosomal localization of BRCA2. Finally, by microinjection of an anti-BRCA2 antibody into the cytoplasm of HeLa S3 cells, we found that depletion of normal BRCA2 proteins in the cytoplasm leads to centrosome amplification and binucleated cells. Our results suggest that disruption of the NES function by genetic changes results in deregulation of BRCA2 export, which ultimately leads to centrosome disorder.
机译：BRCA2基因的生殖系突变导致乳腺癌和卵巢癌的遗传易感性。 BRCA2包含两个核定位信号，主要位于核内，并在DNA双链断裂修复中起重要作用。最近，我们报道了BRCA2在细胞周期的S期和M期早期定位于中心体。在本研究中，我们首次在BRCA2中鉴定了功能性核输出序列（NES1; 1383DLSDLTFLEVA1393）。绿色荧光蛋白（GFP）-NES1融合蛋白位于细胞质中，并可能被染色体区域维持1特异性输出抑制剂瘦霉素B阻断。NES1母体中的亮氨酸残基突变为丙氨酸（L1384A）导致两者GFP-NES1融合蛋白的胞质和核定位以及异位全长BRCA2-FLAG的核积累。而且，用细霉素B处理细胞降低了BRCA2的中心体定位。最后，通过将抗BRCA2抗体显微注射到HeLa S3细胞的细胞质中，我们发现细胞质中正常BRCA2蛋白质的耗尽会导致中心体扩增和双核细胞。我们的结果表明，遗传改变对NES功能的破坏会导致BRCA2输出的失控，最终导致中心体疾病。

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