Bub1 and CENP-U redundantly recruit Plk1 to stabilize kinetochore-microtubule attachments and ensure accurate chromosome segregation
Bub1 and CENP-U redundantly recruit Plk1 to stabilize kinetochore-microtubule attachments and ensure accurate chromosome segregation
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Bub1 和 CENP-U 冗余招募 Plk1 以稳定动粒-微管附着并确保准确的染色体分离
DOI：
10.1016/j.celrep.2021.109740
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发表时间：
2021-09-21
期刊：
影响因子：
8.8
通讯作者：
Yan, Haiyan
中科院分区：
文献类型：
--
作者：
Chen, Qinfu;Zhang, Miao;Yan, Haiyan
Bub 1是两种必需的有丝分裂激酶Plk 1和Aurora B的动粒/着丝粒定位所必需的。令人惊讶的是，在人类细胞中稳定消耗Bub 1接近95%，这对整个染色体分离保真度有轻微影响。我们表明，CENP-U，这是招募到着丝粒的CENP-O复合物的CENP-P和CENP-Q亚基，需要防止染色体错误分离Bub 1耗尽细胞。从机制上讲，Bub 1和CENP-U冗余地将Plk 1招募到着丝粒中以稳定着丝粒微管附着，从而确保准确的染色体分离。此外，不同于其芽殖酵母同源物，CENP-0复合物不调节Aurora B的着丝粒定位。一致地，Bub 1或CENP-U的消耗使细胞对Plk 1的抑制而不是Aurora B激酶活性的抑制敏感。综上所述，我们的研究结果提供了对动粒功能调节的机制性见解，这可能对具有Bub 1或CENP-0复合物干扰Plk 1动粒募集突变的癌细胞的靶向治疗具有影响。
Bub1 is required for the kinetochore/centromere localization of two essential mitotic kinases Plk1 and Aurora B. Surprisingly, stable depletion of Bub1 by similar to 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 kinetochoremicrotubule 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.