Bub1 is required for the kinetochore/centromere localization of two essential mitotic kinases Plk1 and Aurora B. Surprisingly, stable depletion of Bub1 by ∼95% in human cells marginally affects whole chromosome segregation fidelity. We show that CENP-U, which is recruited to kinetochores by the CENP-P and CENP-Q subunits of the CENP-O complex, is required to prevent chromosome mis-segregation in Bub1-depleted cells. Mechanistically, Bub1 and CENP-U redundantly recruit Plk1 to kinetochores to stabilize kinetochore-microtubule attachments, thereby ensuring accurate chromosome segregation. Furthermore, unlike its budding yeast homolog, the CENP-O complex does not regulate centromeric localization of Aurora B. Consistently, depletion of Bub1 or CENP-U sensitizes cells to the inhibition of Plk1 but not Aurora B kinase activity. Taken together, our findings provide mechanistic insight into the regulation of kinetochore function, which may have implications for targeted treatment of cancer cells with mutations perturbing kinetochore recruitment of Plk1 by Bub1 or the CENP-O complex.

Bub1 是两种必需的有丝分裂激酶 Plk1 和 Aurora B 的动粒/着丝粒定位所必需的。令人惊讶的是，人类细胞中 Bub1 稳定消耗约 95% 会略微影响整个染色体分离保真度。我们表明，CENP-U 被 CENP-O 复合体的 CENP-P 和 CENP-Q 亚基募集到动粒中，是防止 Bub1 耗尽细胞中染色体错误分离所必需的。从机制上讲，Bub1 和 CENP-U 多余地将 Plk1 募集到动粒以稳定动粒-微管附件，从而确保准确的染色体分离。此外，与其出芽酵母同系物不同，CENP-O 复合物不调节 Aurora B 的着丝粒定位。始终如一地，Bub1 或 CENP-U 的消耗使细胞对 Plk1 的抑制敏感，但对 Aurora B 激酶活性不敏感。综合起来，