Correcting improper chromosome-spindle attachments during cell division.
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.
Lampson
Michael A
MA
Laboratory of Chemistry and Cell Biology, Rockefeller University, New York, NY 10021, USA.
Renduchitala
Kishore
K
Khodjakov
Alexey
A
Kapoor
Tarun M
TM
D000818:Animals; D064127:Aurora Kinases; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D020090:Chromosome Segregation / Q000187:drug effects / Q000502:physiology*; D002875:Chromosomes / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D049452:Green Fluorescent Proteins; D018386:Kinetochores / Q000201:enzymology; D008164:Luminescent Proteins; D018613:Microscopy, Confocal; D008870:Microtubules / Q000201:enzymology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D008941:Spindle Apparatus / Q000187:drug effects / Q000502:physiology*; D013871:Thiones / Q000494:pharmacology
D004791:Enzyme Inhibitors; D008164:Luminescent Proteins; D011743:Pyrimidines; D013871:Thiones; D049452:Green Fluorescent Proteins; C400223:monastrol; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases