Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN 55905, USA.
J Cell Biol. 2012 Dec 10;199(6):931-49. doi: 10.1083/jcb.201205115. Epub 2012 Dec 3.
The mitotic checkpoint protein Bub1 is essential for embryogenesis and survival of proliferating cells, and bidirectional deviations from its normal level of expression cause chromosome missegregation, aneuploidy, and cancer predisposition in mice. To provide insight into the physiological significance of this critical mitotic regulator at a modular level, we generated Bub1 mutant mice that lack kinase activity using a knockin gene-targeting approach that preserves normal protein abundance. In this paper, we uncover that Bub1 kinase activity integrates attachment error correction and mitotic checkpoint signaling by controlling the localization and activity of Aurora B kinase through phosphorylation of histone H2A at threonine 121. Strikingly, despite substantial chromosome segregation errors and aneuploidization, mice deficient for Bub1 kinase activity do not exhibit increased susceptibility to spontaneous or carcinogen-induced tumorigenesis. These findings provide a unique example of a modular mitotic activity orchestrating two distinct networks that safeguard against whole chromosome instability and reveal the differential importance of distinct aneuploidy-causing Bub1 defects in tumor suppression.
有丝分裂检查点蛋白 Bub1 对于胚胎发生和增殖细胞的存活是必不可少的，其表达水平的双向偏离会导致小鼠的染色体错误分离、非整倍体和癌症易感性。为了在模块水平上深入了解这个关键的有丝分裂调节剂的生理意义，我们使用基因靶向敲入方法生成了缺乏激酶活性的 Bub1 突变小鼠，该方法保留了正常的蛋白丰度。在本文中，我们揭示了 Bub1 激酶活性通过磷酸化组蛋白 H2A 第 121 位丝氨酸来控制 Aurora B 激酶的定位和活性，从而整合了附着错误校正和有丝分裂检查点信号。引人注目的是，尽管存在大量的染色体分离错误和非整倍体化，缺乏 Bub1 激酶活性的小鼠并没有增加对自发或致癌物诱导的肿瘤发生的易感性。这些发现为模块化有丝分裂活性协调两个不同的网络提供了一个独特的例子，该网络可防止全染色体不稳定性，并揭示了不同的导致非整倍体的 Bub1 缺陷在肿瘤抑制中的不同重要性。
