Insufficiency of BUBR1, a mitotic spindle checkpoint regulator, causes impaired ciliogenesis in vertebrates
Insufficiency of BUBR1, a mitotic spindle checkpoint regulator, causes impaired ciliogenesis in vertebrates
复制标题
DOI：
10.1093/hmg/ddr090
复制
发表时间：
2011-05-15
影响因子：
3.5
通讯作者：
Matsuura, Shinya
中科院分区：
文献类型：
--
作者：
Miyamoto, Tatsuo;Porazinski, Sean;Matsuura, Shinya
不受苯并咪唑相关蛋白1（BUBR 1）抑制的出芽是纺锤体组装检查点的中心分子。不受编码BUBR 1的苯并咪唑类1同系物β基因抑制的出芽中的生殖系突变导致过早染色单体分离（镶嵌杂色非整倍性）[PCS（MVA）]综合征，其特征在于体质性非整倍性和儿童癌症的高风险。患有该综合征的患者通常会出现Dandy-Walker综合征和多囊性肾;这意味着BUBR 1在形态发生中起着关键作用。然而，很少有人知道BUBR 1的功能以外的有丝分裂控制。在这里，我们报告说，BUBR 1是必不可少的初级纤毛形成，PCS（MVA）综合征，因此是一种新的纤毛病变。在青鳉鱼中，bubr 1的吗啉代敲除也引起纤毛功能障碍，其特征在于小脑发育缺陷和胚胎左右不对称。生化分析表明，BUBR 1是必需的泛素介导的蛋白酶体降解细胞分裂周期蛋白20在G 0期，并保持后期促进复合物/cyclosome-CDC 20同系物1的活性，调节最佳水平的凌乱纤毛发生。
Budding uninhibited by benzimidazole-related 1 (BUBR1) is a central molecule of the spindle assembly checkpoint. Germline mutations in the budding uninhibited by benzimidazoles 1 homolog beta gene encoding BUBR1 cause premature chromatid separation (mosaic variegated aneuploidy) [PCS (MVA)] syndrome, which is characterized by constitutional aneuploidy and a high risk of childhood cancer. Patients with the syndrome often develop Dandy-Walker complex and polycystic kidneys; implying a critical role of BUBR1 in morphogenesis. However, little is known about the function of BUBR1 other than mitotic control. Here, we report that BUBR1 is essential for the primary cilium formation, and that the PCS (MVA) syndrome is thus a novel ciliopathy. Morpholino knockdown of bubr1 in medaka fish also caused ciliary dysfunction characterized by defects in cerebellar development and perturbed left-right asymmetry of the embryo. Biochemical analyses demonstrated that BUBR1 is required for ubiquitin-mediated proteasomal degradation of cell division cycle protein 20 in the G0 phase and maintains anaphase-promoting complex/cyclosome-CDC20 homolog 1 activity that regulates the optimal level of dishevelled for ciliogenesis.