ISSN 0253-2778

CN 34-1054/N

Open AccessOpen Access JUSTC Life Sciences 15 May 2023

The function, structure and dynamic organization of centromeres and kinetochores

Cite this:
https://doi.org/10.52396/JUSTC-2022-0184
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  • Author Bio:

    Zhen Dou received his Ph.D. degree in Cell Biology from the University of Science and Technology of China. He is currently an Associate Professor at the University of Science and Technology of China. His research interests include cell division cycle and genome stability maintenance

    Xing Liu is a Professor of MOE Key Laboratory for Cellular Dynamics at the University of Science and Technology of China. She received her Ph.D. degree in Cell Biology from the University of Science and Technology of China. Her research mainly focuses on solving the key scientific questions and challenges of cell fate decision using chemical tools and methods

  • Corresponding author: E-mail: douzhen@ustc.edu.cn; E-mail: xing1017@ustc.edu.cn
  • Received Date: 27 December 2022
  • Accepted Date: 07 April 2023
  • Available Online: 15 May 2023
  • It is a fundamental task to ensure the faithful transmission of genetic information across generations for eukaryote species. The centromere is a specialized chromosomal region that is essential for mediating sister chromatid alignment and separation during mitosis. Centromere identity is epigenetically determined by nucleosome-containing centromere protein A (CENP-A). The CENP-A nucleosome provides the foundation for the association of the inner kinetochore and the assembly of the outer kinetochore in mitosis. Here we review centromere identity determination, inner kinetochore function and assembly, and outer kinetochore function and assembly. In particular, we focus on the recent advances in the structure-activity relationship of the constitutive centromere-associated network (CCAN). CCAN structure information sheds new light on our understanding of centromere and kinetochore functions and dynamic organization.
    Schematic representation of a mitotic spindle and the organization of core proteins of inner and outer kinetochore.
    It is a fundamental task to ensure the faithful transmission of genetic information across generations for eukaryote species. The centromere is a specialized chromosomal region that is essential for mediating sister chromatid alignment and separation during mitosis. Centromere identity is epigenetically determined by nucleosome-containing centromere protein A (CENP-A). The CENP-A nucleosome provides the foundation for the association of the inner kinetochore and the assembly of the outer kinetochore in mitosis. Here we review centromere identity determination, inner kinetochore function and assembly, and outer kinetochore function and assembly. In particular, we focus on the recent advances in the structure-activity relationship of the constitutive centromere-associated network (CCAN). CCAN structure information sheds new light on our understanding of centromere and kinetochore functions and dynamic organization.
    • Centromere is a vital macromolecular machinery for cell renewal quality control.
    • CENP-A nucleosome is the hallmark and foundation for centromere and kinetochore assembly.
    • Centromere and kinetochore core complex CCAN undergoes dynamic remodeling from CENP-A nucleosome-elicited loading to DNA-centric gripping upon assembly.
    • The excitement and challenge ahead are to illuminate the spatiotemporal characteristics of CCAN assembly in situ at atomic resolution.

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  • [1]
    McAinsh A D, Marston A L. The four causes: The functional architecture of centromeres and kinetochores. Annu. Rev. Genet., 2022, 56: 279–314. doi: 10.1146/annurev-genet-072820-034559
    [2]
    Biggins S. The composition, functions, and regulation of the budding yeast kinetochore. Genetics, 2013, 194 (4): 817–846. doi: 10.1534/genetics.112.145276
    [3]
    Lawrimore J, Bloom K S, Salmon E D. Point centromeres contain more than a single centromere-specific Cse4 (CENP-A) nucleosome. J. Cell Biol., 2011, 195 (4): 573–582. doi: 10.1083/jcb.201106036
    [4]
    Coffman V C, Wu P C, Parthun M R, et al. CENP-A exceeds microtubule attachment sites in centromere clusters of both budding and fission yeast. J. Cell Biol., 2011, 195 (4): 563–572. doi: 10.1083/jcb.201106078
    [5]
    Haase J, Mishra P K, Stephens A, et al. A 3D map of the yeast kinetochore reveals the presence of core and accessory centromere-specific histone. Curr. Biol., 2013, 23 (19): 1939–1944. doi: 10.1016/j.cub.2013.07.083
    [6]
    Cieslinski K, Wu Y L, Nechyporenko L, et al. Nanoscale structural organization and stoichiometry of the budding yeast kinetochore. J. Cell Biol., 2023, 222 (4): e202209094. doi: 10.1083/jcb.202209094
    [7]
    Cleveland D W, Mao Y, Sullivan K F. Centromeres and kinetochores: From epigenetics to mitotic checkpoint signaling. Cell, 2003, 112 (4): 407–421. doi: 10.1016/S0092-8674(03)00115-6
    [8]
    Allshire R C, Karpen G H. Epigenetic regulation of centromeric chromatin: old dogs, new tricks? Nat. Rev. Genet., 2008, 9 (12): 923–937. doi: 10.1038/nrg2466
    [9]
    Steiner F A, Henikoff S. Holocentromeres are dispersed point centromeres localized at transcription factor hotspots. eLife, 2014, 3: e02025. doi: 10.7554/eLife.02025
    [10]
    Kixmoeller K, Allu P K, Black B E. The centromere comes into focus: from CENP-A nucleosomes to kinetochore connections with the spindle. Open Biol., 2020, 10 (6): 200051. doi: 10.1098/rsob.200051
    [11]
    Black B E, Foltz D R, Chakravarthy S, et al. Structural determinants for generating centromeric chromatin. Nature, 2004, 430 (6999): 578–582. doi: 10.1038/nature02766
    [12]
    Sekulic N, Bassett E A, Rogers D J, et al. The structure of (CENP-A-H4)2 reveals physical features that mark centromeres. Nature, 2010, 467 (7313): 347–351. doi: 10.1038/nature09323
    [13]
    Jansen L E T, Black B E, Foltz D R, et al. Propagation of centromeric chromatin requires exit from mitosis. J. Cell Biol., 2007, 176 (6): 795–805. doi: 10.1083/jcb.200701066
    [14]
    Foltz D R, Jansen L E T, Bailey A O, et al. Centromere-specific assembly of CENP-A nucleosomes is mediated by HJURP. Cell, 2009, 137 (3): 472–484. doi: 10.1016/j.cell.2009.02.039
    [15]
    Dunleavy E M, Roche D, Tagami H, et al. HJURP is a cell-cycle-dependent maintenance and deposition factor of CENP-A at centromeres. Cell, 2009, 137 (3): 485–497. doi: 10.1016/j.cell.2009.02.040
    [16]
    Wang J Y, Liu X, Dou Z, et al. Mitotic regulator Mis18β interacts with and specifies the centromeric assembly of molecular chaperone holliday junction recognition protein (HJURP). J. Biol. Chem., 2014, 289 (12): 8326–8336. doi: 10.1074/jbc.M113.529958
    [17]
    Stankovic A, Guo L Y, Mata J F, et al. A dual inhibitory mechanism sufficient to maintain cell-cycle-restricted CENP-A assembly. Mol. Cell, 2017, 65 (2): 231–246. doi: 10.1016/j.molcel.2016.11.021
    [18]
    Pesenti M E, Weir J R, Musacchio A. Progress in the structural and functional characterization of kinetochores. Curr. Opin. Struct. Biol., 2016, 37: 152–163. doi: 10.1016/j.sbi.2016.03.003
    [19]
    Dou Z, Prifti D K, Gui P, et al. Recent progress on the localization of the spindle assembly checkpoint machinery to kinetochores. Cells, 2019, 8 (3): 278. doi: 10.3390/cells8030278
    [20]
    Carmena M, Wheelock M, Funabiki H, et al. The chromosomal passenger complex (CPC): from easy rider to the godfather of mitosis. Nat. Rev. Mol. Cell Biol., 2012, 13 (12): 789–803. doi: 10.1038/nrm3474
    [21]
    Carroll C W, Silva M C C, Godek K M, et al. Centromere assembly requires the direct recognition of CENP-A nucleosomes by CENP-N. Nat. Cell Biol., 2009, 11 (7): 896–902. doi: 10.1038/ncb1899
    [22]
    Hinshaw S M, Harrison S C. An Iml3-Chl4 heterodimer links the core centromere to factors required for accurate chromosome segregation. Cell Rep., 2013, 5 (1): 29–36. doi: 10.1016/j.celrep.2013.08.036
    [23]
    McKinley K L, Sekulic N, Guo L Y, et al. The CENP-L-N complex forms a critical node in an integrated meshwork of interactions at the centromere-kinetochore interface. Mol. Cell, 2015, 60 (6): 886–898. doi: 10.1016/j.molcel.2015.10.027
    [24]
    Carroll C W, Milks K J, Straight A F. Dual recognition of CENP-A nucleosomes is required for centromere assembly. J. Cell Biol., 2010, 189 (7): 1143–1155. doi: 10.1083/jcb.201001013
    [25]
    Guse A, Carroll C W, Moree B, et al. In vitro centromere and kinetochore assembly on defined chromatin templates. Nature, 2011, 477 (7364): 354–358. doi: 10.1038/nature10379
    [26]
    Tachiwana H, Kagawa W, Shiga T, et al. Crystal structure of the human centromeric nucleosome containing CENP-A. Nature, 2011, 476 (7359): 232–235. doi: 10.1038/nature10258
    [27]
    Fang J N, Liu Y T, Wei Y, et al. Structural transitions of centromeric chromatin regulate the cell cycle-dependent recruitment of CENP-N. Genes Dev., 2015, 29 (10): 1058–1073. doi: 10.1101/gad.259432.115
    [28]
    Tian T, Li X R, Liu Y Y, et al. Molecular basis for CENP-N recognition of CENP-A nucleosome on the human kinetochore. Cell Res., 2018, 28 (3): 374–378. doi: 10.1038/cr.2018.13
    [29]
    Chittori S, Hong J, Saunders H, et al. Structural mechanisms of centromeric nucleosome recognition by the kinetochore protein CENP-N. Science, 2018, 359 (6373): 339–343. doi: 10.1126/science.aar2781
    [30]
    Pentakota S, Zhou K, Smith C, et al. Decoding the centromeric nucleosome through CENP-N. eLife, 2017, 6: e33442. doi: 10.7554/eLife.33442
    [31]
    Yan K, Yang J, Zhang Z, et al. Structure of the inner kinetochore CCAN complex assembled onto a centromeric nucleosome. Nature, 2019, 574 (7777): 278–282. doi: 10.1038/s41586-019-1609-1
    [32]
    Tian T, Chen L, Dou Z, et al. Structural insights into human CCAN complex assembled onto DNA. Cell Discov., 2022, 8 (1): 90. doi: 10.1038/s41421-022-00439-6
    [33]
    Yatskevich S, Muir K W, Bellini D, et al. Structure of the human inner kinetochore bound to a centromeric CENP-A nucleosome. Science, 2022, 376 (6595): 844–852. doi: 10.1126/science.abn3810
    [34]
    Pesenti M E, Raisch T, Conti D, et al. Structure of the human inner kinetochore CCAN complex and its significance for human centromere organization. Mol. Cell, 2022, 82 (11): 2113–2131.e8. doi: 10.1016/j.molcel.2022.04.027
    [35]
    Moree B, Meyer C B, Fuller C J, et al. CENP-C recruits M18BP1 to centromeres to promote CENP-A chromatin assembly. J. Cell Biol., 2011, 194 (6): 855–871. doi: 10.1083/jcb.201106079
    [36]
    Watanabe R, Hara M, Okumura E I, et al. CDK1-mediated CENP-C phosphorylation modulates CENP-A binding and mitotic kinetochore localization. J. Cell Biol., 2019, 218 (218): 4042–4062. doi: 10.1083/jcb.201907006
    [37]
    Liu, R, Dou, Z, Tian, T, et al. Dynamic phosphorylation of CENP-N by CDK1 guides accurate chromosome segregation in mitosis. J. Mol. Cell Biol., 2023: mjad041. doi: 10.1093/jmcb/mjad041
    [38]
    Navarro A P, Cheeseman I M. Dynamic cell cycle-dependent phosphorylation modulates CENP-L-CENP-N centromere recruitment. Mol. Biol. Cell, 2022, 33 (10): ar87. doi: 10.1091/mbc.E22-06-0239
    [39]
    Singh P, Pesenti M E, Maffini S, et al. BUB1 and CENP-U, primed by CDK1, are the main PLK1 kinetochore receptors in mitosis. Mol. Cell, 2021, 81 (1): 67–87.e9. doi: 10.1016/j.molcel.2020.10.040
    [40]
    Chen Q F, Zhang M, Pan X, et al. Bub1 and CENP-U redundantly recruit Plk1 to stabilize kinetochore-microtubule attachments and ensure accurate chromosome segregation. Cell Rep., 2021, 36 (12): 109740. doi: 10.1016/j.celrep.2021.109740
    [41]
    Sedzro D M, Yuan X, Mullen M, et al. Phosphorylation of CENP-R by Aurora B regulates kinetochore-microtubule attachment for accurate chromosome segregation. J. Mol. Cell Biol., 2022, 14 (7): mjac051. doi: 10.1093/jmcb/mjac051
    [42]
    Ariyoshi M, Makino F, Watanabe R, et al. Cryo-EM structure of the CENP-A nucleosome in complex with phosphorylated CENP-C. EMBO J., 2021, 40 (5): e105671. doi: 10.15252/embj.2020105671
    [43]
    Böhm M, Killinger K, Dudziak A, et al. Cdc4 phospho-degrons allow differential regulation of Ame1CENP-U protein stability across the cell cycle. eLife, 2021, 10: e67390. doi: 10.7554/eLife.67390
    [44]
    Westermann S, Cheeseman I M, Anderson S, et al. Architecture of the budding yeast kinetochore reveals a conserved molecular core. J. Cell Biol., 2003, 163 (2): 215–222. doi: 10.1083/jcb.200305100
    [45]
    Cheeseman I M, Niessen S, Anderson S, et al. A conserved protein network controls assembly of the outer kinetochore and its ability to sustain tension. Genes Dev., 2004, 18 (18): 2255–2268. doi: 10.1101/gad.1234104
    [46]
    Screpanti E, De Antoni A, Alushin G M, et al. Direct binding of Cenp-C to the Mis12 complex joins the inner and outer kinetochore. Curr. Biol., 2011, 21 (5): 391–398. doi: 10.1016/j.cub.2010.12.039
    [47]
    Przewloka M R, Venkei Z, Bolanos-Garcia V M, et al. CENP-C is a structural platform for kinetochore assembly. Curr. Biol., 2011, 21 (5): 399–405. doi: 10.1016/j.cub.2011.02.005
    [48]
    Petrovic A, Keller J, Liu Y, et al. Structure of the MIS12 complex and molecular basis of its interaction with CENP-C at human kinetochores. Cell, 2016, 167 (4): 1028–1040.e15. doi: 10.1016/j.cell.2016.10.005
    [49]
    Gascoigne K E, Takeuchi K, Suzuki A, et al. Induced ectopic kinetochore assembly bypasses the requirement for CENP-A nucleosomes. Cell, 2011, 145 (3): 410–422. doi: 10.1016/j.cell.2011.03.031
    [50]
    Schleiffer A, Maier M, Litos G, et al. CENP-T proteins are conserved centromere receptors of the Ndc80 complex. Nat. Cell Biol., 2012, 14 (6): 604–613. doi: 10.1038/ncb2493
    [51]
    Gascoigne K E, Cheeseman I M. CDK-dependent phosphorylation and nuclear exclusion coordinately control kinetochore assembly state. J. Cell Biol., 2013, 201 (1): 23–32. doi: 10.1083/jcb.201301006
    [52]
    Nishino T, Rago F, Hori T, et al. CENP-T provides a structural platform for outer kinetochore assembly. EMBO J., 2013, 32 (3): 424–436. doi: 10.1038/emboj.2012.348
    [53]
    Huis In 't Veld P J, Jeganathan S, Petrovic A, et al. Molecular basis of outer kinetochore assembly on CENP-T. eLife, 2016, 5: e21007. doi: 10.7554/eLife.21007
    [54]
    Yang Y, Wu F, Ward T, et al. Phosphorylation of HsMis13 by Aurora B kinase is essential for assembly of functional kinetochore. J. Biol. Chem., 2008, 283 (39): 26726–26736. doi: 10.1074/jbc.M804207200
    [55]
    Dimitrova Y N, Jenni S, Valverde R, et al. Structure of the MIND complex defines a regulatory focus for yeast kinetochore assembly. Cell, 2016, 167 (4): 1014–1027.e12. doi: 10.1016/j.cell.2016.10.011
    [56]
    Zhou X, Zheng F, Wang C L, et al. Phosphorylation of CENP-C by Aurora B facilitates kinetochore attachment error correction in mitosis. Proc. Natl. Acad. Sci. U.S.A., 2017, 114 (50): E10667–E10676. doi: 10.1073/pnas.1710506114
    [57]
    Hara M, Ariyoshi M, Okumura E I, et al. Multiple phosphorylations control recruitment of the KMN network onto kinetochores. Nat. Cell Biol., 2018, 20 (12): 1378–1388. doi: 10.1038/s41556-018-0230-0
    [58]
    Foley E A, Kapoor T M. Microtubule attachment and spindle assembly checkpoint signalling at the kinetochore. Nat. Rev. Mol. Cell Biol., 2013, 14 (1): 25–37. doi: 10.1038/nrm3494
    [59]
    Nijenhuis W, von Castelmur E, Littler D, et al. A TPR domain-containing N-terminal module of MPS1 is required for its kinetochore localization by Aurora B. J. Cell Biol., 2013, 201 (2): 217–231. doi: 10.1083/jcb.201210033
    [60]
    Dou Z, Liu X, Wang W W, et al. Dynamic localization of Mps1 kinase to kinetochores is essential for accurate spindle microtubule attachment. Proc. Natl. Acad. Sci. U.S.A., 2015, 112 (33): E4546–E4555. doi: 10.1073/pnas.1508791112
    [61]
    Hiruma Y, Sacristan C, Pachis S T, et al. Competition between MPS1 and microtubules at kinetochores regulates spindle checkpoint signaling. Science, 2015, 348 (6240): 1264–1267. doi: 10.1126/science.aaa4055
    [62]
    Ji Z, Gao H, Yu H. Kinetochore attachment sensed by competitive Mps1 and microtubule binding to Ndc80C. Science, 2015, 348 (6240): 1260–1264. doi: 10.1126/science.aaa4029
    [63]
    Primorac I, Weir J R, Chiroli E, et al. Bub3 reads phosphorylated MELT repeats to promote spindle assembly checkpoint signaling. eLife, 2013, 2: e01030. doi: 10.7554/eLife.01030
    [64]
    Ji Z, Gao H, Jia L, et al. A sequential multitarget Mps1 phosphorylation cascade promotes spindle checkpoint signaling. eLife, 2017, 6: e22513. doi: 10.7554/eLife.22513
    [65]
    Rodriguez-Rodriguez J A, Lewis C, McKinley K L, et al. Distinct roles of RZZ and Bub1-KNL1 in mitotic checkpoint signaling and kinetochore expansion. Curr. Biol., 2018, 28 (21): 3422–3429.e5. doi: 10.1016/j.cub.2018.10.006
    [66]
    Alfonso-Pérez T, Hayward D, Holder J, et al. MAD1-dependent recruitment of CDK1-CCNB1 to kinetochores promotes spindle checkpoint signaling. J. Cell Biol., 2019, 218 (4): 1108–1117. doi: 10.1083/jcb.201808015
    [67]
    Allan L A, Reis M C, Ciossani G, et al. Cyclin B1 scaffolds MAD1 at the kinetochore corona to activate the mitotic checkpoint. EMBO J., 2020, 39 (12): e103180. doi: 10.15252/embj.2019103180
    [68]
    Jackman M, Marcozzi C, Barbiero M, et al. Cyclin B1-Cdk1 facilitates MAD1 release from the nuclear pore to ensure a robust spindle checkpoint. J. Cell Biol., 2020, 219 (6): e201907082. doi: 10.1083/jcb.201907082
    [69]
    Liu S K, Yuan X, Cui P, et al. Mad2 promotes Cyclin B2 recruitment to the kinetochore for guiding accurate mitotic checkpoint. EMBO Rep., 2022, 23 (6): e54171. doi: 10.15252/embr.202154171
    [70]
    Liu X, Liu X, Wang H W, et al. Phase separation drives decision making in cell division. J Biol. Chem., 2020, 295 (39): 13419–13431. doi: 10.1074/jbc.REV120.011746
    [71]
    Xia P, Liu X, Wu B, et al. Superresolution imaging reveals structural features of EB1 in microtubule plus-end tracking. Mol. Biol. Cell, 2014, 25 (25): 4166–4173. doi: 10.1091/mbc.E14-06-1133
    [72]
    Huang Y J, Lin L, Liu X, et al. BubR1 phosphorylates CENP-E as a switch enabling the transition from lateral association to end-on capture of spindle microtubules. Cell Res., 2019, 29 (7): 562–578. doi: 10.1038/s41422-019-0178-z
    [73]
    Song X Y, Yang F R, Liu X, et al. Dynamic crotonylation of EB1 by TIP60 ensures accurate spindle positioning in mitosis. Nat. Chem. Biol., 2021, 17 (12): 1314–1323. doi: 10.1038/s41589-021-00875-7
    [74]
    Song X Y, Yang F R, Yang T T, et al. Phase separation of EB1 guides microtubule plus-end dynamics. Nat. Cell Biol., 2023, 25 (1): 79–91. doi: 10.1038/s41556-022-01033-4
    [75]
    Meier S M, Farcas A M, Kumar A, et al. Multivalency ensures persistence of a +TIP body at specialized microtubule ends. Nat. Cell Biol., 2023, 25 (1): 56–67. doi: 10.1038/s41556-022-01035-2
    [76]
    Maan R, Reese L, Volkov V A, et al. Multivalent interactions facilitate motor-dependent protein accumulation at growing microtubule plus-ends. Nat. Cell Biol., 2023, 25 (1): 68–78. doi: 10.1038/s41556-022-01037-0
    [77]
    Zhang S W, Zou S T, Yin D Y, et al. USP14-regulated allostery of the human proteasome by time-resolved cryo-EM. Nature, 2022, 605 (7910): 567–574. doi: 10.1038/s41586-022-04671-8
    [78]
    Ly P, Brunner S F, Shoshani O, et al. Chromosome segregation errors generate a diverse spectrum of simple and complex genomic rearrangements. Nat. Genet., 2019, 51 (4): 705–715. doi: 10.1038/s41588-019-0360-8
    [79]
    Yao X B, Smolka A J. Gastric parietal cell physiology and Helicobacter pylori-induced disease. Gastroenterology, 2019, 156 (8): 2158–2173. doi: 10.1053/j.gastro.2019.02.036
  • 加载中

Catalog

    Figure  1.  A cartoon shown mitotic spindle and the chromosomes. In the central position of the spindle, two chromosomes achieved correct microtubule attachment. On the contrary, a chromosome near the left pole failed to establish proper microtubule attachment. Thus, the kinetochores of this unaligned chromosome initiate a signaling call the spindle assembly checkpoint (SAC) and thereafter preclude the cell to enter anaphase. The yellow dots on chromosomes depict centromeres, and the red dots depict kinetochores.

    Figure  2.  The structure of inner kinetochore and outer kinetochore core proteins. Centromeric CENP-A nucleosome serves as the foundation for kinetochore assembly. CCAN, a complex comprising 16 proteins, constitutively localizes at the centromeres. The cartoon shows the 3D architecture of CCAN bound CENP-A nucleosome. Interestingly, CCAN forms a channel that topologically grasps linker DNA of CENP-A nucleosome. CENP-T and CENP-C, which both have an elongated N-terminal tail, functions as two parallel pathways to recruit Knl1 complex, Mis12 complex and Ndc80 complex in mitosis. Knl1 complex, Mis12 complex and Ndc80 complex comprise the core of outer kinetochore and were named KMN network. KMN harbors two activity, attaching the spindle microtubule and recruiting SAC signaling proteins.

    Figure  3.  DNA binds to CCAN through the CENP-LN channel[32]. (a) Electrostatic potential surface view of CENP-LN-HIK head-TW binding with DNA. The DNA is shown as cartoon. Note that positively charged amino acids from CENPLN, CENP-I and CENP-TW constitute the contact sites between CCAN and DNA. (b) Representative immunofluorescence montage of HeLa cells expressing GFPCENP-L wild type and DNA binding-deficient mutants. 4KA represents CENP-L K155A/R306A/K319A/K321A, 4KE represents K155E/R306E/K319E/K321E. Scale bar, 10 μm. (c) Statistical analysis of kinetochore intensity of various GFP-CENP-L mutants as treated in b. Bars represent the mean kinetochore intensity (±SEM) normalized to values of the CENP-L WT expressing group. Each dot represents one cell (30 cells from three independent experiments). Ordinary one-way ANOVA followed by Tukey’s post hoc test was used to determine statistical significance. ****p < 0.0001.

    [1]
    McAinsh A D, Marston A L. The four causes: The functional architecture of centromeres and kinetochores. Annu. Rev. Genet., 2022, 56: 279–314. doi: 10.1146/annurev-genet-072820-034559
    [2]
    Biggins S. The composition, functions, and regulation of the budding yeast kinetochore. Genetics, 2013, 194 (4): 817–846. doi: 10.1534/genetics.112.145276
    [3]
    Lawrimore J, Bloom K S, Salmon E D. Point centromeres contain more than a single centromere-specific Cse4 (CENP-A) nucleosome. J. Cell Biol., 2011, 195 (4): 573–582. doi: 10.1083/jcb.201106036
    [4]
    Coffman V C, Wu P C, Parthun M R, et al. CENP-A exceeds microtubule attachment sites in centromere clusters of both budding and fission yeast. J. Cell Biol., 2011, 195 (4): 563–572. doi: 10.1083/jcb.201106078
    [5]
    Haase J, Mishra P K, Stephens A, et al. A 3D map of the yeast kinetochore reveals the presence of core and accessory centromere-specific histone. Curr. Biol., 2013, 23 (19): 1939–1944. doi: 10.1016/j.cub.2013.07.083
    [6]
    Cieslinski K, Wu Y L, Nechyporenko L, et al. Nanoscale structural organization and stoichiometry of the budding yeast kinetochore. J. Cell Biol., 2023, 222 (4): e202209094. doi: 10.1083/jcb.202209094
    [7]
    Cleveland D W, Mao Y, Sullivan K F. Centromeres and kinetochores: From epigenetics to mitotic checkpoint signaling. Cell, 2003, 112 (4): 407–421. doi: 10.1016/S0092-8674(03)00115-6
    [8]
    Allshire R C, Karpen G H. Epigenetic regulation of centromeric chromatin: old dogs, new tricks? Nat. Rev. Genet., 2008, 9 (12): 923–937. doi: 10.1038/nrg2466
    [9]
    Steiner F A, Henikoff S. Holocentromeres are dispersed point centromeres localized at transcription factor hotspots. eLife, 2014, 3: e02025. doi: 10.7554/eLife.02025
    [10]
    Kixmoeller K, Allu P K, Black B E. The centromere comes into focus: from CENP-A nucleosomes to kinetochore connections with the spindle. Open Biol., 2020, 10 (6): 200051. doi: 10.1098/rsob.200051
    [11]
    Black B E, Foltz D R, Chakravarthy S, et al. Structural determinants for generating centromeric chromatin. Nature, 2004, 430 (6999): 578–582. doi: 10.1038/nature02766
    [12]
    Sekulic N, Bassett E A, Rogers D J, et al. The structure of (CENP-A-H4)2 reveals physical features that mark centromeres. Nature, 2010, 467 (7313): 347–351. doi: 10.1038/nature09323
    [13]
    Jansen L E T, Black B E, Foltz D R, et al. Propagation of centromeric chromatin requires exit from mitosis. J. Cell Biol., 2007, 176 (6): 795–805. doi: 10.1083/jcb.200701066
    [14]
    Foltz D R, Jansen L E T, Bailey A O, et al. Centromere-specific assembly of CENP-A nucleosomes is mediated by HJURP. Cell, 2009, 137 (3): 472–484. doi: 10.1016/j.cell.2009.02.039
    [15]
    Dunleavy E M, Roche D, Tagami H, et al. HJURP is a cell-cycle-dependent maintenance and deposition factor of CENP-A at centromeres. Cell, 2009, 137 (3): 485–497. doi: 10.1016/j.cell.2009.02.040
    [16]
    Wang J Y, Liu X, Dou Z, et al. Mitotic regulator Mis18β interacts with and specifies the centromeric assembly of molecular chaperone holliday junction recognition protein (HJURP). J. Biol. Chem., 2014, 289 (12): 8326–8336. doi: 10.1074/jbc.M113.529958
    [17]
    Stankovic A, Guo L Y, Mata J F, et al. A dual inhibitory mechanism sufficient to maintain cell-cycle-restricted CENP-A assembly. Mol. Cell, 2017, 65 (2): 231–246. doi: 10.1016/j.molcel.2016.11.021
    [18]
    Pesenti M E, Weir J R, Musacchio A. Progress in the structural and functional characterization of kinetochores. Curr. Opin. Struct. Biol., 2016, 37: 152–163. doi: 10.1016/j.sbi.2016.03.003
    [19]
    Dou Z, Prifti D K, Gui P, et al. Recent progress on the localization of the spindle assembly checkpoint machinery to kinetochores. Cells, 2019, 8 (3): 278. doi: 10.3390/cells8030278
    [20]
    Carmena M, Wheelock M, Funabiki H, et al. The chromosomal passenger complex (CPC): from easy rider to the godfather of mitosis. Nat. Rev. Mol. Cell Biol., 2012, 13 (12): 789–803. doi: 10.1038/nrm3474
    [21]
    Carroll C W, Silva M C C, Godek K M, et al. Centromere assembly requires the direct recognition of CENP-A nucleosomes by CENP-N. Nat. Cell Biol., 2009, 11 (7): 896–902. doi: 10.1038/ncb1899
    [22]
    Hinshaw S M, Harrison S C. An Iml3-Chl4 heterodimer links the core centromere to factors required for accurate chromosome segregation. Cell Rep., 2013, 5 (1): 29–36. doi: 10.1016/j.celrep.2013.08.036
    [23]
    McKinley K L, Sekulic N, Guo L Y, et al. The CENP-L-N complex forms a critical node in an integrated meshwork of interactions at the centromere-kinetochore interface. Mol. Cell, 2015, 60 (6): 886–898. doi: 10.1016/j.molcel.2015.10.027
    [24]
    Carroll C W, Milks K J, Straight A F. Dual recognition of CENP-A nucleosomes is required for centromere assembly. J. Cell Biol., 2010, 189 (7): 1143–1155. doi: 10.1083/jcb.201001013
    [25]
    Guse A, Carroll C W, Moree B, et al. In vitro centromere and kinetochore assembly on defined chromatin templates. Nature, 2011, 477 (7364): 354–358. doi: 10.1038/nature10379
    [26]
    Tachiwana H, Kagawa W, Shiga T, et al. Crystal structure of the human centromeric nucleosome containing CENP-A. Nature, 2011, 476 (7359): 232–235. doi: 10.1038/nature10258
    [27]
    Fang J N, Liu Y T, Wei Y, et al. Structural transitions of centromeric chromatin regulate the cell cycle-dependent recruitment of CENP-N. Genes Dev., 2015, 29 (10): 1058–1073. doi: 10.1101/gad.259432.115
    [28]
    Tian T, Li X R, Liu Y Y, et al. Molecular basis for CENP-N recognition of CENP-A nucleosome on the human kinetochore. Cell Res., 2018, 28 (3): 374–378. doi: 10.1038/cr.2018.13
    [29]
    Chittori S, Hong J, Saunders H, et al. Structural mechanisms of centromeric nucleosome recognition by the kinetochore protein CENP-N. Science, 2018, 359 (6373): 339–343. doi: 10.1126/science.aar2781
    [30]
    Pentakota S, Zhou K, Smith C, et al. Decoding the centromeric nucleosome through CENP-N. eLife, 2017, 6: e33442. doi: 10.7554/eLife.33442
    [31]
    Yan K, Yang J, Zhang Z, et al. Structure of the inner kinetochore CCAN complex assembled onto a centromeric nucleosome. Nature, 2019, 574 (7777): 278–282. doi: 10.1038/s41586-019-1609-1
    [32]
    Tian T, Chen L, Dou Z, et al. Structural insights into human CCAN complex assembled onto DNA. Cell Discov., 2022, 8 (1): 90. doi: 10.1038/s41421-022-00439-6
    [33]
    Yatskevich S, Muir K W, Bellini D, et al. Structure of the human inner kinetochore bound to a centromeric CENP-A nucleosome. Science, 2022, 376 (6595): 844–852. doi: 10.1126/science.abn3810
    [34]
    Pesenti M E, Raisch T, Conti D, et al. Structure of the human inner kinetochore CCAN complex and its significance for human centromere organization. Mol. Cell, 2022, 82 (11): 2113–2131.e8. doi: 10.1016/j.molcel.2022.04.027
    [35]
    Moree B, Meyer C B, Fuller C J, et al. CENP-C recruits M18BP1 to centromeres to promote CENP-A chromatin assembly. J. Cell Biol., 2011, 194 (6): 855–871. doi: 10.1083/jcb.201106079
    [36]
    Watanabe R, Hara M, Okumura E I, et al. CDK1-mediated CENP-C phosphorylation modulates CENP-A binding and mitotic kinetochore localization. J. Cell Biol., 2019, 218 (218): 4042–4062. doi: 10.1083/jcb.201907006
    [37]
    Liu, R, Dou, Z, Tian, T, et al. Dynamic phosphorylation of CENP-N by CDK1 guides accurate chromosome segregation in mitosis. J. Mol. Cell Biol., 2023: mjad041. doi: 10.1093/jmcb/mjad041
    [38]
    Navarro A P, Cheeseman I M. Dynamic cell cycle-dependent phosphorylation modulates CENP-L-CENP-N centromere recruitment. Mol. Biol. Cell, 2022, 33 (10): ar87. doi: 10.1091/mbc.E22-06-0239
    [39]
    Singh P, Pesenti M E, Maffini S, et al. BUB1 and CENP-U, primed by CDK1, are the main PLK1 kinetochore receptors in mitosis. Mol. Cell, 2021, 81 (1): 67–87.e9. doi: 10.1016/j.molcel.2020.10.040
    [40]
    Chen Q F, Zhang M, Pan X, et al. Bub1 and CENP-U redundantly recruit Plk1 to stabilize kinetochore-microtubule attachments and ensure accurate chromosome segregation. Cell Rep., 2021, 36 (12): 109740. doi: 10.1016/j.celrep.2021.109740
    [41]
    Sedzro D M, Yuan X, Mullen M, et al. Phosphorylation of CENP-R by Aurora B regulates kinetochore-microtubule attachment for accurate chromosome segregation. J. Mol. Cell Biol., 2022, 14 (7): mjac051. doi: 10.1093/jmcb/mjac051
    [42]
    Ariyoshi M, Makino F, Watanabe R, et al. Cryo-EM structure of the CENP-A nucleosome in complex with phosphorylated CENP-C. EMBO J., 2021, 40 (5): e105671. doi: 10.15252/embj.2020105671
    [43]
    Böhm M, Killinger K, Dudziak A, et al. Cdc4 phospho-degrons allow differential regulation of Ame1CENP-U protein stability across the cell cycle. eLife, 2021, 10: e67390. doi: 10.7554/eLife.67390
    [44]
    Westermann S, Cheeseman I M, Anderson S, et al. Architecture of the budding yeast kinetochore reveals a conserved molecular core. J. Cell Biol., 2003, 163 (2): 215–222. doi: 10.1083/jcb.200305100
    [45]
    Cheeseman I M, Niessen S, Anderson S, et al. A conserved protein network controls assembly of the outer kinetochore and its ability to sustain tension. Genes Dev., 2004, 18 (18): 2255–2268. doi: 10.1101/gad.1234104
    [46]
    Screpanti E, De Antoni A, Alushin G M, et al. Direct binding of Cenp-C to the Mis12 complex joins the inner and outer kinetochore. Curr. Biol., 2011, 21 (5): 391–398. doi: 10.1016/j.cub.2010.12.039
    [47]
    Przewloka M R, Venkei Z, Bolanos-Garcia V M, et al. CENP-C is a structural platform for kinetochore assembly. Curr. Biol., 2011, 21 (5): 399–405. doi: 10.1016/j.cub.2011.02.005
    [48]
    Petrovic A, Keller J, Liu Y, et al. Structure of the MIS12 complex and molecular basis of its interaction with CENP-C at human kinetochores. Cell, 2016, 167 (4): 1028–1040.e15. doi: 10.1016/j.cell.2016.10.005
    [49]
    Gascoigne K E, Takeuchi K, Suzuki A, et al. Induced ectopic kinetochore assembly bypasses the requirement for CENP-A nucleosomes. Cell, 2011, 145 (3): 410–422. doi: 10.1016/j.cell.2011.03.031
    [50]
    Schleiffer A, Maier M, Litos G, et al. CENP-T proteins are conserved centromere receptors of the Ndc80 complex. Nat. Cell Biol., 2012, 14 (6): 604–613. doi: 10.1038/ncb2493
    [51]
    Gascoigne K E, Cheeseman I M. CDK-dependent phosphorylation and nuclear exclusion coordinately control kinetochore assembly state. J. Cell Biol., 2013, 201 (1): 23–32. doi: 10.1083/jcb.201301006
    [52]
    Nishino T, Rago F, Hori T, et al. CENP-T provides a structural platform for outer kinetochore assembly. EMBO J., 2013, 32 (3): 424–436. doi: 10.1038/emboj.2012.348
    [53]
    Huis In 't Veld P J, Jeganathan S, Petrovic A, et al. Molecular basis of outer kinetochore assembly on CENP-T. eLife, 2016, 5: e21007. doi: 10.7554/eLife.21007
    [54]
    Yang Y, Wu F, Ward T, et al. Phosphorylation of HsMis13 by Aurora B kinase is essential for assembly of functional kinetochore. J. Biol. Chem., 2008, 283 (39): 26726–26736. doi: 10.1074/jbc.M804207200
    [55]
    Dimitrova Y N, Jenni S, Valverde R, et al. Structure of the MIND complex defines a regulatory focus for yeast kinetochore assembly. Cell, 2016, 167 (4): 1014–1027.e12. doi: 10.1016/j.cell.2016.10.011
    [56]
    Zhou X, Zheng F, Wang C L, et al. Phosphorylation of CENP-C by Aurora B facilitates kinetochore attachment error correction in mitosis. Proc. Natl. Acad. Sci. U.S.A., 2017, 114 (50): E10667–E10676. doi: 10.1073/pnas.1710506114
    [57]
    Hara M, Ariyoshi M, Okumura E I, et al. Multiple phosphorylations control recruitment of the KMN network onto kinetochores. Nat. Cell Biol., 2018, 20 (12): 1378–1388. doi: 10.1038/s41556-018-0230-0
    [58]
    Foley E A, Kapoor T M. Microtubule attachment and spindle assembly checkpoint signalling at the kinetochore. Nat. Rev. Mol. Cell Biol., 2013, 14 (1): 25–37. doi: 10.1038/nrm3494
    [59]
    Nijenhuis W, von Castelmur E, Littler D, et al. A TPR domain-containing N-terminal module of MPS1 is required for its kinetochore localization by Aurora B. J. Cell Biol., 2013, 201 (2): 217–231. doi: 10.1083/jcb.201210033
    [60]
    Dou Z, Liu X, Wang W W, et al. Dynamic localization of Mps1 kinase to kinetochores is essential for accurate spindle microtubule attachment. Proc. Natl. Acad. Sci. U.S.A., 2015, 112 (33): E4546–E4555. doi: 10.1073/pnas.1508791112
    [61]
    Hiruma Y, Sacristan C, Pachis S T, et al. Competition between MPS1 and microtubules at kinetochores regulates spindle checkpoint signaling. Science, 2015, 348 (6240): 1264–1267. doi: 10.1126/science.aaa4055
    [62]
    Ji Z, Gao H, Yu H. Kinetochore attachment sensed by competitive Mps1 and microtubule binding to Ndc80C. Science, 2015, 348 (6240): 1260–1264. doi: 10.1126/science.aaa4029
    [63]
    Primorac I, Weir J R, Chiroli E, et al. Bub3 reads phosphorylated MELT repeats to promote spindle assembly checkpoint signaling. eLife, 2013, 2: e01030. doi: 10.7554/eLife.01030
    [64]
    Ji Z, Gao H, Jia L, et al. A sequential multitarget Mps1 phosphorylation cascade promotes spindle checkpoint signaling. eLife, 2017, 6: e22513. doi: 10.7554/eLife.22513
    [65]
    Rodriguez-Rodriguez J A, Lewis C, McKinley K L, et al. Distinct roles of RZZ and Bub1-KNL1 in mitotic checkpoint signaling and kinetochore expansion. Curr. Biol., 2018, 28 (21): 3422–3429.e5. doi: 10.1016/j.cub.2018.10.006
    [66]
    Alfonso-Pérez T, Hayward D, Holder J, et al. MAD1-dependent recruitment of CDK1-CCNB1 to kinetochores promotes spindle checkpoint signaling. J. Cell Biol., 2019, 218 (4): 1108–1117. doi: 10.1083/jcb.201808015
    [67]
    Allan L A, Reis M C, Ciossani G, et al. Cyclin B1 scaffolds MAD1 at the kinetochore corona to activate the mitotic checkpoint. EMBO J., 2020, 39 (12): e103180. doi: 10.15252/embj.2019103180
    [68]
    Jackman M, Marcozzi C, Barbiero M, et al. Cyclin B1-Cdk1 facilitates MAD1 release from the nuclear pore to ensure a robust spindle checkpoint. J. Cell Biol., 2020, 219 (6): e201907082. doi: 10.1083/jcb.201907082
    [69]
    Liu S K, Yuan X, Cui P, et al. Mad2 promotes Cyclin B2 recruitment to the kinetochore for guiding accurate mitotic checkpoint. EMBO Rep., 2022, 23 (6): e54171. doi: 10.15252/embr.202154171
    [70]
    Liu X, Liu X, Wang H W, et al. Phase separation drives decision making in cell division. J Biol. Chem., 2020, 295 (39): 13419–13431. doi: 10.1074/jbc.REV120.011746
    [71]
    Xia P, Liu X, Wu B, et al. Superresolution imaging reveals structural features of EB1 in microtubule plus-end tracking. Mol. Biol. Cell, 2014, 25 (25): 4166–4173. doi: 10.1091/mbc.E14-06-1133
    [72]
    Huang Y J, Lin L, Liu X, et al. BubR1 phosphorylates CENP-E as a switch enabling the transition from lateral association to end-on capture of spindle microtubules. Cell Res., 2019, 29 (7): 562–578. doi: 10.1038/s41422-019-0178-z
    [73]
    Song X Y, Yang F R, Liu X, et al. Dynamic crotonylation of EB1 by TIP60 ensures accurate spindle positioning in mitosis. Nat. Chem. Biol., 2021, 17 (12): 1314–1323. doi: 10.1038/s41589-021-00875-7
    [74]
    Song X Y, Yang F R, Yang T T, et al. Phase separation of EB1 guides microtubule plus-end dynamics. Nat. Cell Biol., 2023, 25 (1): 79–91. doi: 10.1038/s41556-022-01033-4
    [75]
    Meier S M, Farcas A M, Kumar A, et al. Multivalency ensures persistence of a +TIP body at specialized microtubule ends. Nat. Cell Biol., 2023, 25 (1): 56–67. doi: 10.1038/s41556-022-01035-2
    [76]
    Maan R, Reese L, Volkov V A, et al. Multivalent interactions facilitate motor-dependent protein accumulation at growing microtubule plus-ends. Nat. Cell Biol., 2023, 25 (1): 68–78. doi: 10.1038/s41556-022-01037-0
    [77]
    Zhang S W, Zou S T, Yin D Y, et al. USP14-regulated allostery of the human proteasome by time-resolved cryo-EM. Nature, 2022, 605 (7910): 567–574. doi: 10.1038/s41586-022-04671-8
    [78]
    Ly P, Brunner S F, Shoshani O, et al. Chromosome segregation errors generate a diverse spectrum of simple and complex genomic rearrangements. Nat. Genet., 2019, 51 (4): 705–715. doi: 10.1038/s41588-019-0360-8
    [79]
    Yao X B, Smolka A J. Gastric parietal cell physiology and Helicobacter pylori-induced disease. Gastroenterology, 2019, 156 (8): 2158–2173. doi: 10.1053/j.gastro.2019.02.036

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