Correcting improper chromosome-spindle attachments during cell division

Nat Cell Biol. 2004 Mar;6(3):232-7. doi: 10.1038/ncb1102. Epub 2004 Feb 8.

Abstract

For accurate segregation of chromosomes during cell division, microtubule fibres must attach sister kinetochores to opposite poles of the mitotic spindle (bi-orientation). Aurora kinases are linked to oncogenesis and have been implicated in the regulation of chromosome-microtubule attachments. Although loss of Aurora kinase activity causes an accumulation of mal-orientated chromosomes in dividing cells, it is not known how the active kinase corrects improper chromosome attachments. The use of reversible small-molecule inhibitors allows activation of protein function in living vertebrate cells with temporal control. Here we show that by removal of small-molecule inhibitors, controlled activation of Aurora kinase during mitosis can correct chromosome attachment errors by selective disassembly of kinetochore-microtubule fibres, rather than by alternative mechanisms involving initial release of microtubules from either kinetochores or spindle poles. Observation of chromosomes and microtubule dynamics with real-time high-resolution microscopy showed that mal-orientated, but not bi-orientated, chromosomes move to the spindle pole as both kinetochore-microtubule fibres shorten, followed by alignment at the metaphase plate. Our results provide direct evidence for a mechanism required for the maintenance of genome integrity during cell division.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Aurora Kinases
  • Cell Division / drug effects
  • Cell Division / physiology
  • Cell Line
  • Chromosome Segregation / drug effects
  • Chromosome Segregation / physiology*
  • Chromosomes / drug effects
  • Chromosomes / physiology*
  • Enzyme Inhibitors / pharmacology
  • Green Fluorescent Proteins
  • Kinetochores / enzymology
  • Luminescent Proteins
  • Microscopy, Confocal
  • Microtubules / enzymology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / metabolism*
  • Pyrimidines / pharmacology
  • Spindle Apparatus / drug effects
  • Spindle Apparatus / physiology*
  • Thiones / pharmacology

Substances

  • Enzyme Inhibitors
  • Luminescent Proteins
  • Pyrimidines
  • Thiones
  • Green Fluorescent Proteins
  • monastrol
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases