title: Chromosome misalignments induce spindle-positioning defects.
abstract: Cortical pulling forces on astral microtubules are essential to position the spindle. These forces are generated by cortical dynein, a minus-end directed motor. Previously, another dynein regulator termed Spindly was proposed to regulate dynein-dependent spindle positioning. However, the mechanism of how Spindly regulates spindle positioning has remained elusive. Here, we find that the misalignment of chromosomes caused by Spindly depletion is directly provoking spindle misorientation. Chromosome misalignments induced by CLIP-170 or CENP-E depletion or by noscapine treatment are similarly accompanied by severe spindle-positioning defects. We find that cortical LGN is actively displaced from the cortex when misaligned chromosomes are in close proximity. Preventing the KT recruitment of Plk1 by the depletion of PBIP1 rescues cortical LGN enrichment near misaligned chromosomes and re-establishes proper spindle orientation. Hence, KT-enriched Plk1 is responsible for the negative regulation of cortical LGN localization. In summary, we uncovered a compelling molecular link between chromosome alignment and spindle orientation defects, both of which are implicated in tumorigenesis.
authors.affiliation: Department of Cell Biology and Cancer Genomics Center, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Mihoko A
authors.initials: MA
authors.lastname: Tame
authors.affiliation: Department of Cell Biology and Cancer Genomics Center, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Jonne A
authors.initials: JA
authors.lastname: Raaijmakers
authors.affiliation: The Maastricht Multimodal Molecular Imaging Institute, Maastricht University, Maastricht, The Netherlands.
authors.forename: Pavel
authors.initials: P
authors.lastname: Afanasyev
authors.affiliation: Department of Cell Biology and Cancer Genomics Center, The Netherlands Cancer Institute, Amsterdam, The Netherlands r.medema@nki.nl.
authors.forename: René H
authors.initials: RH
authors.lastname: Medema
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D023902:Chromosome Pairing; D045584:Chromosome Positioning; D006367:HeLa Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D008941:Spindle Apparatus / Q000378:metabolism* / Q000648:ultrastructure; D000097869:Polo-Like Kinase 1
chemical_list: D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C102754:GPSM2 protein, human; C549402:SPDL1 protein, human; C068688:centromere protein E; C076744:cytoplasmic linker protein 170
keywords: LGN; PLK1; chromosome misalignment; micropatterning; spindle positioning