BRCA2 Fine-Tunes the Spindle Assembly Checkpoint through Reinforcement of BubR1 Acetylation
BRCA2 Fine-Tunes the Spindle Assembly Checkpoint through Reinforcement of BubR1 Acetylation
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DOI：
10.1016/j.devcel.2012.01.009
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发表时间：
2012-02-14
影响因子：
11.8
通讯作者：
Lee, Hyunsook
中科院分区：
文献类型：
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作者：
Choi, Eunhee;Park, Pil-Gu;Lee, Hyunsook
使BRCA2失活的生殖系突变会促进染色体不稳定的早发性癌症。在这里，我们报告BRCA2调节主轴组件检查点(SAC)。此前，我们报道了BubR1乙酰化对SAC活性是必不可少的。在这项研究中，我们显示BRCA2招募PCAF乙酰转移酶，并在有丝分裂过程中帮助BubR1乙酰化。在没有BRCA2的情况下，有丝分裂过程中BubR1乙酰化被取消，BubR1水平下降。同样，BRCA2缺陷的小鼠胚胎成纤维细胞表现出弱的SAC活性。被设计为BRCA2-BubR1关联中断的转基因小鼠表现出显著的BubR1乙酰化减少，SAC活性减弱，以及非整倍体。这些转基因小鼠在40%的外显率下发生了自发肿瘤。此外，对人乳腺癌标本的免疫组织化学分析表明，8RCA2突变与BubR1状态密切相关。我们的结果为BRCA2突变如何导致染色体不稳定提供了解释，而SAC组分没有明显的突变。
Germ line mutations that inactivate BRCA2 promote early-onset cancer with chromosome instability. Here, we report that BRCA2 regulates the spindle assembly checkpoint (SAC). Previously, we reported that BubR1 acetylation is essential for SAC activity. In this study we show that BRCA2 recruits the PCAF acetyltransferase and aids in BubR1 acetylation during mitosis. In the absence of BRCA2, BubR1 acetylation is abolished, and the level of BubR1 decreases during mitosis. Similarly, Brca2-deficient mouse embryonic fibroblasts exhibited weak SAC activity. Transgenic mice that were engineered to have interruptions in the BRCA2-BubR1 association exhibited marked decrease of BubR1 acetylation, weakened SAC activity, and aneuploidy. These transgenic mice developed spontaneous tumors at 40% penetrance. Moreover, immunohistochemical analyses of human breast cancer specimens suggested that 8RCA2 mutation and BubR1 status is closely linked. Our results provide an explanation for how mutation of BRCA2 can lead to chromosome instability without apparent mutations in SAC components.