Kinetochores often form merotelic attachments, in which a single kinetochore is attached to microtubules from both spindle poles. These attachments can result in improper chromosome segregation and are a significant source of aneuploidy, a hallmark of cancer. Aurora B kinase and the kinesin-13 microtubule depolymerase mitotic-centromere-associated kinesin (MCAK) are required to release improper microtubule attachments. Aurora B regulates MCAK's activity and localization. We set out to understand why MCAK and Aurora B are more abundant at some metaphase-aligned centromeres but are present at low amounts on most others. We found that members of the Aurora B complex are specifically enriched at merotelic attachment sites. We also found that Aurora B does not require its activity to become enriched at these sites; however, inhibition of Aurora B activity causes a significant increase in the number of merotelic attachments per cell. Aurora B activity enriches MCAK at merotelic attachments and phosphorylates MCAK on residues that regulate its microtubule depolymerase activity. These data demonstrate that proteins that resolve the defect are specifically localized to merotelic attachments, where their enzymatic activities are regulated.
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http://dx.doi.org/10.1016/j.cub.2006.07.057 | DOI Listing |
J Mol Cell Biol
October 2024
School of Biological Sciences, The University of Hong Kong, Kadoorie Biological Sciences Building, Pokfulam Road, Hong Kong, China.
Cell
June 2024
Oncode Institute, Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), and University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address:
Centromeres are scaffolds for the assembly of kinetochores that ensure chromosome segregation during cell division. How vertebrate centromeres obtain a three-dimensional structure to accomplish their primary function is unclear. Using super-resolution imaging, capture-C, and polymer modeling, we show that vertebrate centromeres are partitioned by condensins into two subdomains during mitosis.
View Article and Find Full Text PDFGenes (Basel)
January 2024
Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
Cells with an abnormal number of chromosomes have been found in more than 90% of solid tumors, and among these, polyploidy accounts for about 40%. Polyploidized cells most often have duplicate centrosomes as well as genomes, and thus their mitosis tends to promote merotelic spindle attachments and chromosomal instability, which produces a variety of aneuploid daughter cells. Polyploid cells have been found highly resistant to various stress and anticancer therapies, such as radiation and mitogenic inhibitors.
View Article and Find Full Text PDFJ Cell Biol
March 2024
Biology Department, University of Massachusetts, Amherst, MA, USA.
Kinetochores connect chromosomes and spindle microtubules to maintain genomic integrity through cell division. Crosstalk between the minus-end directed motor dynein and kinetochore-microtubule attachment factors promotes accurate chromosome segregation by a poorly understood pathway. Here, we identify a linkage between the intrinsically disordered protein Spc105 (KNL1 orthologue) and dynein using an optogenetic oligomerization assay.
View Article and Find Full Text PDFChromosome Res
July 2023
Department of Biological Sciences and Fralin Life Sciences Institute, Virginia Tech, Blacksburg, VA, 24061, USA.
Micronuclei, small DNA-containing structures separate from the main nucleus, were used for decades as an indicator of genotoxic damage. Micronuclei containing whole chromosomes were considered a biomarker of aneuploidy and were believed to form, upon mitotic exit, from chromosomes that lagged behind in anaphase as all other chromosomes segregated to the poles of the mitotic spindle. However, the mechanism responsible for inducing anaphase lagging chromosomes remained unknown until just over twenty years ago.
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