Chromosome instability in tumor cells due to defects in Aurora B mediated error correction at kinetochores

Abstract

ABSTRACTWe characterized a panel of cancer cells and found that they exhibited chromosome instability (CIN) that was associated with high frequencies of aberrant kinetochore:microtubule attachments. Failure to resolve these defective attachments before anaphase onset can lead to missegregation of chromosomes. Aurora B kinase is concentrated at the inner centromere where it contributes to multiple kinetochore functions, one of which is in error-correction. Analysis of several CIN cell lines showed that many aspects of Aurora B kinase functions were normal. Furthermore, the amount and activity of Aurora B kinase was not reduced at the kinetochores of CIN cells that were examined. However, phosphorylation of a centromeric biosensor for Aurora B in OVCAR10, MCF7 and U2OS cells was consistently reduced relative to non CIN cells. This suggested a localized problem with Aurora B’s ability to phosphorylate substrates important for error correction. This possibility was supported by our ability to improve error correction and reduce the frequency of lagging chromosome in CIN cells by directing endogenous Aurora B to the region of centromere that was tested by the biosensor. Our studies suggest that the kinetochores of CIN cells have a defect that limits accessibility of Aurora B to substrates that are important for error-correction.