Stabilization of MCRS1 by BAP1 prevents chromosome instability in renal cell carcinoma
Stabilization of MCRS1 by BAP1 prevents chromosome instability in renal cell carcinoma
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BAP1 对 MCRS1 的稳定可防止肾细胞癌中的染色体不稳定。
DOI：
10.1016/j.canlet.2015.08.013
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发表时间：
2015-12-01
期刊：
影响因子：
9.7
通讯作者：
Fan, Jie
中科院分区：
文献类型：
--
作者：
Peng, Jingtao;Ma, Jian;Fan, Jie
通过下一代测序鉴定肿瘤的外显子组和基因组(CcRCC)发现了大量的基因改变。BRCA1相关蛋白-1(BAP1)是ccRCC中最常见的突变基因之一，提示BAP1可能是ccRCC发生和发展的关键驱动因素。然而，BAP1突变在肾小管细胞癌中的作用仍有待阐明。BAP1是一种核脱泛素酶，它能从底物上断裂泛素链。在这里，我们确定MCRS1是BAP1的真正底物。MCRS1是中心体蛋白的组成部分，在纺锤体组装过程中起着至关重要的作用。BAP1与MCRS1结合，通过去泛素化稳定MCRS1。BAP1部分通过MCRS1对染色体稳定性起作用。BAP1和MCRS1在肾细胞癌组织中的表达呈正相关。CcRCC中BAPI缺失和MCRS1表达下调均与不良的临床病理特征相关。本研究揭示了BAP1参与MCRS1稳定性调节的新机制，并为了解BAP1突变与肾细胞癌染色体不稳定性的关系提供了新的思路。(C)2015爱思唯尔爱尔兰有限公司。保留所有权利。
Characterization of the exome and genome of carcinoma (ccRCC) by next-generation sequencing identified numerous genetic alternations. BRCA1-associated protein-1 (BAP1) was identified as one of the most frequently mutated genes in ccRCC, suggesting that BAP1 is a potential key driver for ccRCC cancer initiation and progression. However, how BAP1 mutations contribute to ccRCC remains to be elucidated. BAP1 is a nuclear de-ubiquitinating enzyme and cleaves the ubiquitin chain from the substrates. Here, we identified MCRS1 as a bona fide substrate for BAP1. MCRS1 is a component of the centrosome proteins, and plays an essential role in spindle assembly. BAP1 binds to MCRS1 and stabilizes MCRS1 by de-ubiquitination. BAP1 contributes to chromosome stability partially via MCRS1. A positive correlation was identified between BAP1 and MCRS1 expression in ccRCC tissues. Both BAPI loss and MCRS1 downregulation in ccRCC were associated with adverse clinicopathological features. This study revealed a novel mechanism for BAP1 involved in MCRS1 stability regulation, and provided insight in understanding the relationship between BAP1 mutations and chromosome instability in ccRCC. (C) 2015 Elsevier Ireland Ltd. All rights reserved.