BUBR1, a mitotic spindle checkpoint regulator, regulates ciliogenesis in vertebrates.

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  • 分裂期チェックポイント分子BUBR1は脊椎動物における繊毛形成を制御する

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Genomic stability in higher organisms is established by elaborate DNA repair systems and cell cycle checkpoints. We try to dissect the molecular pathology of human genomic instability diseases in order to understand the protective mechanism against various stresses such as ionizing radiation. <BR> BUBR1 is a central molecule of the mitotic spindle assembly checkpoint. Germline mutations in the BUB1B gene encoding BUBR1 cause premature chromatid separation (mosaic variegated aneupoidy)[PCS(MVA)]syndrome, which is characterizes by constitutional aneuploidy and a high risk of childhood cancer. Patient 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 molecular function of BUBR1 other than mitotic control. <BR> Here we report that BUBR1 is essential for the primary cilium; a microtubule-based organelle on the surface of most vertebrate cells in G0 phase, and that PCS(MVA) is thus a novel ciliopathy. Morpholino knockdown of bubr1 in medaka fish also caused ciliary dysfuncion 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 CDC20 in the G0 phase and maintains anaphase-promoting complex/cyclosome (APC/C)-CDH1 activity that regulates the optimal level of dishevelled for ciliogenesis.

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