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PreprintCited by 120Microtubule and mitosis dynamicsGenomics and Chromatin DynamicsNuclear Structure and Function

Structure of the human inner kinetochore bound to a centromeric CENP-A nucleosome

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Yatskevich, Stanislau, Muir, Kyle W., Bellini, Dom, Zhang, Ziguo, Yang, Jing, Tischer, Thomas, Predin, Masa, Dendooven, Tom, McLaughlin, Stephen H., Barford, David·2022·Science
DOI 10.1101/2022.01.07.475394PMC PMC7612757

Preprint — published as 10.1126/science.abn3810 · Paper page

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Abstract

Accurate chromosome segregation, controlled by kinetochore-mediated chromatid attachments to the mitotic spindle, ensures the faithful inheritance of genetic information. Kinetochores assemble onto specialized CENP-A nucleosomes (CENP-A Nuc ) of centromeric chromatin. In humans, this is mostly organized as thousands of copies of an ∼171 bp α -satellite repeat. Here, we describe the cryo-EM structure of the human inner kinetochore CCAN (Constitutive Centromere Associated Network) complex bound to CENP-A Nuc reconstituted onto α-satellite DNA. CCAN forms edge-on contacts with CENP-A Nuc , while a linker DNA segment of the α-satellite repeat emerges from the fully-wrapped end of the nucleosome to thread through the central CENP-LN channel which tightly grips the DNA. The CENP-TWSX histone-fold module, together with CENP-HIK Head , further augments DNA binding and partially wraps the linker DNA in a manner reminiscent of canonical nucleosomes. Our study suggests that the topological entrapment of the α -satellite repeat linker DNA by CCAN provides a robust mechanism by which the kinetochore withstands the pushing and pulling of centromeres associated with chromosome congression and segregation forces. One-Sentence Summary: The human inner kinetochore CCAN complex tightly grips the linker DNA of the α-satellite CENP-A nucleosome.

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Authors
Yatskevich, S., Muir, K. W., Bellini, D., Zhang, Z., Yang, J., Tischer, T., Predin, M., Dendooven, T., McLaughlin, S. H., & Barford, D.
Affiliations
MRC Laboratory of Molecular Biology (GB)
Corresponding author
Barford, David
ORCID
Venue
Science
Publisher
openRxiv
Published
2022-01-08
Volume
376
Issue
6595
Pages
844-852
ISSN
0036-8075 (ISSN-L)
DOI
10.1101/2022.01.07.475394
PMC
PMC7612757
OpenAlex
W4226083267
Cited by
120
References
1
Citations by year
2026: 19 · 2025: 34 · 2024: 29 · 2023: 25 · 2022: 13
FWCI
15.08
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Science (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Diamond Light Source
  • Cancer Research UK (24307, DRCRPG-Jun22\100004)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
Keywords
inner kinetochore, CCAN, alpha-satellite DNA, linker DNA, DNA binding, kinetochore structure, centromere
MeSH terms
Centromere Protein A, Centromere, DNA, Humans, Nucleosomes, Protein Binding, Kinetochores, Cryoelectron Microscopy

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