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TIP60 acetylation of Bub1 regulates centromeric H2AT120 phosphorylation for faithful chromosome segregation

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Abstract

Proper function of the centromeres ensures correct attachment of kinetochores to spindle microtubules and faithful chromosome segregation in mitosis. Defects in the integrity and function of centromeres can result in chromosome missegregation and genomic instability. Bub1 is essential for the mitotic centromere dynamics, yet the underlying molecular mechanisms remain largely unclear. Here, we demonstrate that TIP60 acetylates Bub1 at K424 and K431 on kinetochores in early mitosis. This acetylation increases the kinase activity of Bub1 to phosphorylate centromeric histone H2A at T120 (H2ApT120), which recruits Aurora B and Shugoshin 1 (Sgo1) to regulate centromere integrity, protect centromeric cohesion, and ensure the subsequent faithful chromosome segregation. Expression of the non-acetylated Bub1 mutant reduces its kinase activity, decreases the level of H2ApT120, and disrupts the recruitment of centromere proteins and chromosome congression, leading to genomic instability of daughter cells. When cells exit mitosis, HDAC1-regulated deacetylation of Bub1 decreases H2ApT120 levels and thereby promotes the departure of centromeric CPC and Sgo1, ensuring timely centromeres disassembly. Collectively, our results reveal a molecular mechanism by which the acetylation and deacetylation cycle of Bub1 modulates the phosphorylation of H2A at T120 for recruitment of Aurora B and Sgo1 to the centromeres, ensuring faithful chromosome segregation during mitosis.

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Acknowledgement

We thank Drs. Xuebiao Yao and Xing Liu (University of Science and Technology of China) for providing the HDAC2, SIRT1, SIRT2 and SIRT3 genes. We thank the Flow Cytometry Core at National Center for Protein Sciences at Peking University, particularly Drs. Hongxia Lv, Liying Du and Jia Luo, for technical help with cell sorting. We thank Dr. Dong Liu, for technical help with mass spectrometry, and Dr Siying Qin, for technical help with confocal microscopy, both at National Center for Protein Sciences at Peking University. We also thank all the other members of our laboratories at Kunming University of Science and Technology and Peking University for their constructive suggestions. This work was supported by grants from the National Natural Science Foundation of China (32130026, 92254305 and 32070714).

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  1. The Academy for Cell and Life Health, Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, 650500, China

    Mengjie Sun & Chuanmao Zhang

  2. The Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, Beijing, 100871, China

    Mengjie Sun, Biying Yang, Guangwei Xin, Yao Wang, Jia Luo, Qing Jiang & Chuanmao Zhang

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  1. Mengjie Sun
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Sun, M., Yang, B., Xin, G. et al. TIP60 acetylation of Bub1 regulates centromeric H2AT120 phosphorylation for faithful chromosome segregation. Sci. China Life Sci. (2024). https://doi.org/10.1007/s11427-023-2604-8

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