XAB2 functions in mitotic cell cycle progression via transcriptional regulation of CENPE.
XAB2 functions in mitotic cell cycle progression via transcriptional regulation of CENPE.
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XAB2 通过 CENPE 的转录调节在有丝分裂细胞周期进程中发挥作用
DOI：
10.1038/cddis.2016.313
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发表时间：
2016-10-13
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
着色性干皮病A组（Xeroderma pigmentosum group A，XPA）结合蛋白2（Xeroderma pigmentosum binding protein 2，XAB 2）是一种多功能蛋白，在转录、转录偶联DNA修复、前体mRNA剪接、同源重组和mRNA输出等过程中发挥重要作用。基因芯片分析XAB 2基因敲除细胞中的基因表达，发现许多基因在有丝分裂细胞周期调控中具有显著的表达变化。荧光激活细胞扫描仪分析证实XAB 2缺失导致细胞停滞在G2/M期，主要是在前期或前中期。活细胞成像进一步揭示，XAB 2敲低诱导严重的有丝分裂缺陷，包括染色体错配和分离缺陷，导致有丝分裂停滞、有丝分裂灾难和随后的细胞死亡。XAB 2缺失下调的最重要的基因是有丝分裂运动蛋白中心体相关蛋白E（CENPE）。敲低CENPE显示出与XAB 2缺失相似的表型，但CENPE敲低后XAB 2耗尽并没有进一步增强细胞周期停滞。CENPE启动子上的荧光素酶测定显示XAB 2的过表达增加荧光素酶活性，而XAB 2缺失导致荧光素酶活性显著降低。进一步的定位揭示了CENPE启动子中XAB 2转录调控所需的区域。ChIP实验表明XAB 2与CENPE启动子相互作用。总之，这些结果支持XAB 2在有丝分裂细胞周期调节中的新功能，该功能部分由CENPE上的转录调节介导。
Xeroderma pigmentosum group A (XPA)-binding protein 2 (XAB2) is a multi-functional protein that plays critical role in processes including transcription, transcription-coupled DNA repair, pre-mRNA splicing, homologous recombination and mRNA export. Microarray analysis on gene expression in XAB2 knockdown cells reveals that many genes with significant change in expression function in mitotic cell cycle regulation. Fluorescence-activated cell scanner analysis confirmed XAB2 depletion led to cell arrest in G2/M phase, mostly at prophase or prometaphase. Live cell imaging further disclosed that XAB2 knockdown induced severe mitotic defects including chromosome misalignment and defects in segregation, leading to mitotic arrest, mitotic catastrophe and subsequent cell death. Among top genes down-regulated by XAB2 depletion is mitotic motor protein centrosome-associated protein E (CENPE). Knockdown CENPE showed similar phenotypes to loss of XAB2, but CENPE knockdown followed by XAB2 depletion did not further enhance cell cycle arrest. Luciferase assay on CENPE promoter showed that overexpression of XAB2 increased luciferase activity, whereas XAB2 depletion resulted in striking reduction of luciferase activity. Further mapping revealed a region in CENPE promoter that is required for the transcriptional regulation by XAB2. Moreover, ChIP assay showed that XAB2 interacted with CENPE promoter. Together, these results support a novel function of XAB2 in mitotic cell cycle regulation, which is partially mediated by transcription regulation on CENPE.
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