CLASPs prevent irreversible multipolarity by ensuring spindle-pole resistance to traction forces during chromosome alignment.
Loss of spindle-pole integrity during mitosis leads to multipolarity independent of centrosome amplification. Multipolar-spindle conformation favours incorrect kinetochore-microtubule attachments, compromising faithful chromosome segregation and daughter-cell viability. Spindle-pole organization influences and is influenced by kinetochore activity, but the molecular nature behind this critical force balance is unknown. CLASPs are microtubule-, kinetochore- and centrosome-associated proteins whose functional perturbation leads to three main spindle abnormalities: monopolarity, short spindles and multipolarity. The first two reflect a role at the kinetochore-microtubule interface through interaction with specific kinetochore partners, but how CLASPs prevent spindle multipolarity remains unclear. Here we found that human CLASPs ensure spindle-pole integrity after bipolarization in response to CENP-E- and Kid-mediated forces from misaligned chromosomes. This function is independent of end-on kinetochore-microtubule attachments and involves the recruitment of ninein to residual pericentriolar satellites. Distinctively, multipolarity arising through this mechanism often persists through anaphase. We propose that CLASPs and ninein confer spindle-pole resistance to traction forces exerted during chromosome congression, thereby preventing irreversible spindle multipolarity and aneuploidy.
Instituto de Biologia Molecular e Celular, Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal.
Elsa
E
Logarinho
Stefano
S
Maffini
Marin
M
Barisic
Andrea
A
Marques
Alberto
A
Toso
Patrick
P
Meraldi
Helder
H
Maiato
D015153:Blotting, Western; D045744:Cell Line, Tumor; D018385:Centrosome / Q000378:metabolism / Q000502:physiology; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism / Q000502:physiology*; D020090:Chromosome Segregation / Q000502:physiology; D015638:Cytochalasin D / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D018386:Kinetochores / Q000378:metabolism / Q000502:physiology; D008677:Metaphase / Q000502:physiology*; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008938:Mitosis / Q000502:physiology; D008954:Models, Biological; D034622:RNA Interference; D008941:Spindle Apparatus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D059008:Time-Lapse Imaging
C497850:CLASP1 protein, human; C497851:CLASP2 protein, human; D002868:Chromosomal Proteins, Non-Histone; D008869:Microtubule-Associated Proteins; C068688:centromere protein E; D049452:Green Fluorescent Proteins; D015638:Cytochalasin D