Structure of the human inner kinetochore CCAN complex and its significance for human centromere organization

Pesenti, M.E.; Raisch, Tobias; Conti, Duccio; Walstein, Kai; Hoffmann, Ingrid; Vogt, Dorothee; Prumbaum, Daniel; Vetter, Ingrid R.; Raunser, Stefan; Musacchio, Andrea

doi:10.1016/j.molcel.2022.04.027

Cited by 66 publications

(83 citation statements)

References 120 publications

(287 reference statements)

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“…Cryo-EM structures of the human ( Pesenti et al, 2022 ; Yatskevich et al, 2022 ) and yeast ( Hinshaw and Harrison, 2019 ; Yan et al, 2019 ) CCAN complexes have greatly aided in our understanding of its structure-function. The CCAN is observed as a defined complex where its subunits interdigitate rather than forming a network of binary interactions.…”

Section: Inner Kinetochore and The Ccanmentioning

confidence: 99%

“…At the inner kinetochore, the linker pathways of CENP-C and CENP-Q Okp1 -U Ame1 contact centromeric chromatin through CENP-A Cse4 ( Figures 2A,C ) ( Anedchenko et al, 2019 ; Ariyoshi et al, 2021 ; Fischböck-Halwachs et al, 2019 ; Kato et al, 2013 ). While, the CENP-T complex has been described to bind centromeric DNA and induce supercoiling in it ( Figure 2B ) ( Hori et al, 2008a ; Nishino et al, 2012 ; Takeuchi et al, 2014 ; Pesenti et al, 2022 ; Yatskevich et al, 2022 ). The multifaceted roles of linker proteins at the kinetochores make them key candidates for regulatory action ( Hara and Fukagawa, 2019 ).…”

Section: Linkages Connecting the Outer Kinetochore To Centromeric Chr...mentioning

confidence: 99%

“…The CENP-T-W and CENP-S-X dimers can form a heterotetrameric nucleosome-like structure that can bind DNA and induce positive super-coiling, unlike conventional nucleosomes that generate negative supercoils at budding yeast mini-chromosomes ( Furuyama and Henikoff, 2009 ; Nishino et al, 2012 ; Takeuchi et al, 2014 ; Pesenti et al, 2022 ; Yatskevich et al, 2022 ). Loss of CENP-S-X has shown not to strongly affect CENP-T-W levels at the kinetochore although CENP-S is sufficient to recruit CENP-T to an ectopic locus ( Amano et al, 2009 ; Nishino et al, 2012 ).…”

Section: Linkages Connecting the Outer Kinetochore To Centromeric Chr...mentioning

confidence: 99%

“…Additionally, even after more than 50 years of studying the kinetochore a wholistic structural picture of this elegant structure has not been understood, while researchers in the field are just beginning to understand its plasticity. However, recent cryo-EM studies of the reconstituted inner kinetochore complex in budding yeast and humans are providing a strong platform for understanding kinetochore architecture and its evolutionary divergence ( Hinshaw and Harrison, 2019 ; Yan et al, 2019 ; Pesenti et al, 2022 ; Yatskevich et al, 2022 ), Although the primary function of the kinetochore is to form load-bearing attachments, the kinetochore has also to control the feedback mechanism for the correction of inaccurate microtubule attachments through the recruitment of the components involved in the error correction mechanism and the spindle assembly checkpoint (SAC) ( Foley and Kapoor, 2013 ; Joglekar and Kukreja, 2017 ; Lara-Gonzalez et al, 2021 ). Additionally, kinetochores are required to ensure their self-preservation across generations at the centromere through CENP-A replenishment ( Black and Cleveland, 2011 ; McKinley and Cheeseman, 2016 ; Mellone and Fachinetti, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…The outer kinetochore functions as the primary site for spindle microtubule-binding and is chiefly made up of the 10-member KMN network comprising the Knl1 complex (Knl1C), Mis12 complex (Mis12C), and Ndc80 complex (Ndc80C) ( Lampert and Westermann, 2011 ; Musacchio and Desai, 2017 ). More recently, the structure of several of these sub-networks of proteins has been resolved and the kinetochore particle reconstituted, although several questions persist ( Akiyoshi et al, 2010 ; Dimitrova et al, 2016 ; Petrovic et al, 2016 ; Weir et al, 2016 ; Hinshaw and Harrison, 2019 ; Yan et al, 2019 ; Pesenti et al, 2022 ; Yatskevich et al, 2022 ). Interestingly, the single kinetochore module present on the budding yeast point centromere seems to occur multivalently across larger regional centromeres where they are observed to form multiple kinetochore-microtubule attachments ( Figure 1B ).…”

Section: Introductionmentioning

confidence: 99%

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Kinetochore Architecture Employs Diverse Linker Strategies Across Evolution

Sridhar

Fukagawa

2022

Front. Cell Dev. Biol.

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The assembly of a functional kinetochore on centromeric chromatin is necessary to connect chromosomes to the mitotic spindle, ensuring accurate chromosome segregation. This connecting function of the kinetochore presents multiple internal and external structural challenges. A microtubule interacting outer kinetochore and centromeric chromatin interacting inner kinetochore effectively confront forces from the external spindle and centromere, respectively. While internally, special inner kinetochore proteins, defined as “linkers,” simultaneously interact with centromeric chromatin and the outer kinetochore to enable association with the mitotic spindle. With the ability to simultaneously interact with outer kinetochore components and centromeric chromatin, linker proteins such as centromere protein (CENP)-C or CENP-T in vertebrates and, additionally CENP-QOkp1-UAme1 in yeasts, also perform the function of force propagation within the kinetochore. Recent efforts have revealed an array of linker pathways strategies to effectively recruit the largely conserved outer kinetochore. In this review, we examine these linkages used to propagate force and recruit the outer kinetochore across evolution. Further, we look at their known regulatory pathways and implications on kinetochore structural diversity and plasticity.

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Section: Inner Kinetochore and The Ccanmentioning

confidence: 99%

Section: Linkages Connecting the Outer Kinetochore To Centromeric Chr...mentioning

confidence: 99%

Section: Linkages Connecting the Outer Kinetochore To Centromeric Chr...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Kinetochore Architecture Employs Diverse Linker Strategies Across Evolution

Sridhar

Fukagawa

2022

Front. Cell Dev. Biol.

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Vertebrate centromere architecture: from chromatin threads to functional structures

Andrade Ruiz,

Kops,

Sacristan

2024

Chromosoma

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Centromeres are chromatin structures specialized in sister chromatid cohesion, kinetochore assembly, and microtubule attachment during chromosome segregation. The regional centromere of vertebrates consists of long regions of highly repetitive sequences occupied by the Histone H3 variant CENP-A, and which are flanked by pericentromeres. The three-dimensional organization of centromeric chromatin is paramount for its functionality and its ability to withstand spindle forces. Alongside CENP-A, key contributors to the folding of this structure include components of the Constitutive Centromere-Associated Network (CCAN), the protein CENP-B, and condensin and cohesin complexes. Despite its importance, the intricate architecture of the regional centromere of vertebrates remains largely unknown. Recent advancements in long-read sequencing, super-resolution and cryo-electron microscopy, and chromosome conformation capture techniques have significantly improved our understanding of this structure at various levels, from the linear arrangement of centromeric sequences and their epigenetic landscape to their higher-order compaction. In this review, we discuss the latest insights on centromere organization and place them in the context of recent findings describing a bipartite higher-order organization of the centromere.

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