Bub1 and CENP-U redundantly recruit Plk1 to stabilize kinetochore-microtubule attachments and ensure accurate chromosome segregation
Qinfu Chen,
Miao Zhang,
Xuan Pan,
Xueying Yuan,
Linli Zhou,
Lu Yan,
Ling-Hui Zeng,
Junfen Xu,
Bing Yang,
Long Zhang,
Jun Huang,
Weiguo Lu,
Tatsuo Fukagawa,
Fangwei Wang,
Haiyan Yan
Affiliations
Qinfu Chen
Department of Pharmacology, Zhejiang University City College, Hangzhou 310015, China; The MOE Key Laboratory of Biosystems Homeostasis & Protection, The Key Laboratory of Cancer Molecular Cell Biology of Zhejiang Province, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
Miao Zhang
The MOE Key Laboratory of Biosystems Homeostasis & Protection, The Key Laboratory of Cancer Molecular Cell Biology of Zhejiang Province, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
Xuan Pan
The MOE Key Laboratory of Biosystems Homeostasis & Protection, The Key Laboratory of Cancer Molecular Cell Biology of Zhejiang Province, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
Xueying Yuan
The MOE Key Laboratory of Biosystems Homeostasis & Protection, The Key Laboratory of Cancer Molecular Cell Biology of Zhejiang Province, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
Linli Zhou
The MOE Key Laboratory of Biosystems Homeostasis & Protection, The Key Laboratory of Cancer Molecular Cell Biology of Zhejiang Province, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
Lu Yan
The MOE Key Laboratory of Biosystems Homeostasis & Protection, The Key Laboratory of Cancer Molecular Cell Biology of Zhejiang Province, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
Ling-Hui Zeng
Department of Pharmacology, Zhejiang University City College, Hangzhou 310015, China
Junfen Xu
Department of Gynecological Oncology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
Bing Yang
The MOE Key Laboratory of Biosystems Homeostasis & Protection, The Key Laboratory of Cancer Molecular Cell Biology of Zhejiang Province, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
Long Zhang
The MOE Key Laboratory of Biosystems Homeostasis & Protection, The Key Laboratory of Cancer Molecular Cell Biology of Zhejiang Province, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
Jun Huang
The MOE Key Laboratory of Biosystems Homeostasis & Protection, The Key Laboratory of Cancer Molecular Cell Biology of Zhejiang Province, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China
Weiguo Lu
Department of Gynecological Oncology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China; Cancer Center, Zhejiang University, Hangzhou 310058, China
Tatsuo Fukagawa
Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan
Fangwei Wang
The MOE Key Laboratory of Biosystems Homeostasis & Protection, The Key Laboratory of Cancer Molecular Cell Biology of Zhejiang Province, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China; Department of Gynecological Oncology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China; Cancer Center, Zhejiang University, Hangzhou 310058, China; Corresponding author
Haiyan Yan
Department of Pharmacology, Zhejiang University City College, Hangzhou 310015, China; Corresponding author
Summary: 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.
