title: Regulation of a dynamic interaction between two microtubule-binding proteins, EB1 and TIP150, by the mitotic p300/CBP-associated factor (PCAF) orchestrates kinetochore microtubule plasticity and chromosome stability during mitosis.
abstract: The microtubule cytoskeleton network orchestrates cellular dynamics and chromosome stability in mitosis. Although tubulin acetylation is essential for cellular plasticity, it has remained elusive how kinetochore microtubule plus-end dynamics are regulated by p300/CBP-associated factor (PCAF) acetylation in mitosis. Here, we demonstrate that the plus-end tracking protein, TIP150, regulates dynamic kinetochore-microtubule attachments by promoting the stability of spindle microtubule plus-ends. Suppression of TIP150 by siRNA results in metaphase alignment delays and perturbations in chromosome biorientation. TIP150 is a tetramer that binds an end-binding protein (EB1) dimer through the C-terminal domains, and overexpression of the C-terminal TIP150 or disruption of the TIP150-EB1 interface by a membrane-permeable peptide perturbs chromosome segregation. Acetylation of EB1-PCAF regulates the TIP150 interaction, and persistent acetylation perturbs EB1-TIP150 interaction and accurate metaphase alignment, resulting in spindle checkpoint activation. Suppression of the mitotic checkpoint serine/threonine protein kinase, BubR1, overrides mitotic arrest induced by impaired EB1-TIP150 interaction, but cells exhibit whole chromosome aneuploidy. Thus, the results identify a mechanism by which the TIP150-EB1 interaction governs kinetochore microtubule plus-end plasticity and establish that the temporal control of the TIP150-EB1 interaction by PCAF acetylation ensures chromosome stability in mitosis.
authors.affiliation: Anhui-MSM Joint Research Group for Cellular Dynamics, Anhui Key Laboratory for Cellular Dynamics and Chemical Biology, and University of Science and Technology of China, Hefei, Anhui 230026, China.
authors.forename: Tarsha
authors.initials: T
authors.lastname: Ward
authors.forename: Ming
authors.initials: M
authors.lastname: Wang
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.forename: Zhikai
authors.initials: Z
authors.lastname: Wang
authors.forename: Peng
authors.initials: P
authors.lastname: Xia
authors.forename: Youjun
authors.initials: Y
authors.lastname: Chu
authors.forename: Xiwei
authors.initials: X
authors.lastname: Wang
authors.forename: Lifang
authors.initials: L
authors.lastname: Liu
authors.forename: Kai
authors.initials: K
authors.lastname: Jiang
authors.forename: Huijuan
authors.initials: H
authors.lastname: Yu
authors.forename: Maomao
authors.initials: M
authors.lastname: Yan
authors.forename: Jianyu
authors.initials: J
authors.lastname: Wang
authors.forename: Donald L
authors.initials: DL
authors.lastname: Hill
authors.forename: Yuejia
authors.initials: Y
authors.lastname: Huang
authors.forename: Tongge
authors.initials: T
authors.lastname: Zhu
authors.forename: Xuebiao
authors.initials: X
authors.lastname: Yao
mesh_terms: D000107:Acetylation; D059447:Cell Cycle Checkpoints / Q000502:physiology; D043171:Chromosomal Instability / Q000502:physiology*; D002877:Chromosomes, Human / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D018386:Kinetochores; D008677:Metaphase / Q000502:physiology*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D008869:Microtubule-Associated Proteins; D017346:Protein Serine-Threonine Kinases; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C500985:MAPRE1 protein, human; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein
keywords: Acetyl Coenzyme A; Cell Cycle; Genomic Instability; Mitosis; Mitotic Spindle