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The kinetochore is a large molecular machine that attaches chromosomes to microtubules and facilitates chromosome segregation. The kinetochore includes submodules that associate with the centromeric DNA and submodules that attach to microtubules. Additional copies of several submodules of the kinetochore are added during anaphase, including the microtubule binding module Ndc80. While the factors governing plasticity are not known, they could include regulation based on microtubule-kinetochore interactions. We report that Fin1 localizes to the microtubule-proximal edge of the kinetochore cluster during anaphase based on single-particle averaging of super-resolution images. Fin1 is required for the assembly of normal levels of Dam1 and Ndc80 submodules. Levels of Ndc80 further depend on the Dam1 microtubule binding complex. Our results suggest the stoichiometry of outer kinetochore submodules is strongly influenced by factors at the kinetochore-microtubule interface such as Fin1 and Dam1, and phosphorylation by cyclin-dependent kinase. Outer kinetochore stoichiometry is remarkably plastic and responsive to microtubule-proximal regulation.
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http://dx.doi.org/10.1083/jcb.201810070 | DOI Listing |
EMBO Rep
August 2025
Laboratory for Chromosome Segregation, RIKEN Center for Biosystems Dynamics Research (BDR), Kobe, Japan.
Bipolar spindle assembly and chromosome biorientation are prerequisites for chromosome segregation during cell division. The kinesin motor KIF11 (also widely known as Eg5) drives spindle bipolarization by sliding antiparallel microtubules bidirectionally, elongating a spherical spindle into a bipolar-shaped structure in acentrosomal oocytes. During meiosis I, this process stretches homologous chromosome pairs, establishing chromosome biorientation at the spindle equator.
View Article and Find Full Text PDFMed Int (Lond)
August 2025
Graduate School of Health Science, Suzuka University of Medical Science, Suzuka, Mie 510-0293, Japan.
Gastric cancer (GC) is classified into four molecular subtypes according to the Epstein-Barr virus-positive status, microsatellite instability, genomic stability and chromosomal instability (CIN). The CIN subtype is characterized by a high frequency of gene amplifications in receptor tyrosine kinases (RTKs) and a poor prognosis. In addition, the CIN subtype often exhibits intratumoral heterogeneity and indicates insensitivity to targeted drugs.
View Article and Find Full Text PDFCurr Biol
August 2025
Laboratory of Biochemistry and Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, 37 Convent Drive, Bethesda, MD 20892, USA. Electronic address:
The constitutive centromere-associated network (CCAN) of the inner kinetochore links CENP-A-containing nucleosomes of the centromere to the outer kinetochore, ensuring accurate chromosome segregation during mitosis. CCAN binding at the centromere is stabilized upon mitotic entry, but the underlying mechanisms remain unclear. Here, we demonstrate that cohesin is essential for CCAN stability.
View Article and Find Full Text PDFbioRxiv
June 2025
Basic Sciences Division, Howard Hughes Medical Institute, Fred Hutchinson Cancer Center, Seattle, WA, 98109 USA.
Kinetochores are megadalton protein machines that harness microtubules to segregate chromosomes during cell division. The kinetochores must assemble after DNA replication during every cell cycle onto specialized regions of chromosomes called centromeres, but the order and regulation of their assembly remains unclear due to the complexity of kinetochore composition and the difficulty resolving individual kinetochores . Here, by adapting a prior single-molecule method for monitoring kinetochore assembly in budding yeast lysates, we identify a sequential order of assembly and uncover previously unknown interdependencies between subcomplexes.
View Article and Find Full Text PDFMol Biol Cell
August 2025
Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, College of Life Sciences, Peking University, Beijing 100871, China.
Genomic integrity in mammalian cells relies on faithful chromosome segregation. Kinetochores capture microtubules and establish robust kinetochore-microtubule attachment to achieve accurate segregation. The MIS12 complex, a tetramer comprising MIS12, DSN1, NSL1, and PMF1, plays a critical role in kinetochore-microtubule attachment.
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