Department of Biological Sciences and Institute of Molecular Biology and Genetics, Seoul National University, 599 Gwanak-Ro, Gwanak-ku, Seoul 151-742, Korea.
Dev Cell. 2012 Feb 14;22(2):295-308. doi: 10.1016/j.devcel.2012.01.009.
Germline 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 BRCA2 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.
胚系中失活 BRCA2 的突变可促进染色体不稳定的早发性癌症。在这里，我们报告 BRCA2 可调节纺锤体组装检查点（SAC）。先前，我们报道 BubR1 的乙酰化对于 SAC 活性是必需的。在这项研究中，我们发现 BRCA2 募集 PCAF 乙酰转移酶并在有丝分裂期间辅助 BubR1 的乙酰化。在缺乏 BRCA2 的情况下，BubR1 的乙酰化被废除，并且在有丝分裂期间 BubR1 的水平降低。同样，Brca2 缺陷型小鼠胚胎成纤维细胞表现出较弱的 SAC 活性。设计用于中断 BRCA2-BubR1 关联的转基因小鼠表现出明显降低的 BubR1 乙酰化、减弱的 SAC 活性和非整倍性。这些转基因小鼠以 40%的外显率自发形成肿瘤。此外，对人乳腺癌标本的免疫组织化学分析表明，BRCA2 突变和 BubR1 状态密切相关。我们的结果解释了为什么 BRCA2 的突变可导致染色体不稳定，而 SAC 成分没有明显突变。
