title: A role for metaphase spindle elongation forces in correction of merotelic kinetochore attachments.
abstract: During mitosis, equal segregation of chromosomes depends on proper kinetochore-microtubule attachments. Merotelic kinetochore orientation, in which a single kinetochore binds microtubules from both spindle poles [1], is a major cause of chromosome instability [2], which is commonly observed in solid tumors [3, 4]. Using the fission yeast Schizosaccharomyces pombe, we show that a proper force balance between kinesin motors on interpolar spindle microtubules is critical for correcting merotelic attachments. Inhibition of the plus-end-directed spindle elongation motors kinesin-5 (Cut7) and kinesin-6 (Klp9) reduces spindle length, tension at kinetochores, and the frequency of merotelic attachments. In contrast, merotely is increased by deletion of the minus-end-directed kinesin-14 (Klp2) or overexpression of Klp9. Also, Cdk1 regulates spindle elongation forces to promote merotelic correction by phosphorylating and inhibiting Klp9. The role of spindle elongation motors in merotelic correction is conserved, because partial inhibition of the human kinesin-5 homolog Eg5 using the drug monastrol reduces spindle length and lagging chromosome frequency in both normal (RPE-1) and tumor (CaCo-2) cells. These findings reveal unexpected links between spindle forces and correction of merotelic attachments and show that pharmacological manipulation of spindle elongation forces might be used to reduce chromosome instability in cancer cells.
authors.affiliation: Department of Microbiology and Physiological Systems and Program in Cell Dynamics, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Sung Hugh
authors.initials: SH
authors.lastname: Choi
authors.forename: Dannel
authors.initials: D
authors.lastname: McCollum
mesh_terms: D016203:CDC2 Protein Kinase / Q000378:metabolism / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics; D002460:Cell Line; D043171:Chromosomal Instability / Q000187:drug effects; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D020090:Chromosome Segregation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D018386:Kinetochores / Q000187:drug effects / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000235:genetics; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology; D012568:Schizosaccharomyces / Q000166:cytology* / Q000235:genetics; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics; D008941:Spindle Apparatus / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D013871:Thiones / Q000494:pharmacology
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; C470243:KIF11 protein, human; C552052:Mde4 protein, S pombe; D009687:Nuclear Proteins; D011743:Pyrimidines; D029702:Schizosaccharomyces pombe Proteins; C465958:Swi6 protein, S pombe; D013871:Thiones; C400223:monastrol; D016203:CDC2 Protein Kinase; C439269:Clp1 protein, S. pombe; D017027:Protein Tyrosine Phosphatases; D016547:Kinesins