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Chromosomes with delayed replication timing lead to checkpoint activation, delayed recruitment of Aurora B and chromosome instability

Oncogene volume 26, pages 1852–1861 (2007)Cite this article

Abstract

Certain chromosome rearrangements display a significant delay in chromosome replication timing (DRT) that is associated with a subsequent delay in mitotic chromosome condensation (DMC). DRT/DMC chromosomes are common in tumor cells in vitro and in vivo and occur frequently in cells exposed to ionizing radiation. A hallmark for these chromosomes is the delayed phosphorylation of serine 10 of histone H3 during mitosis. The chromosome passenger complex, consisting of multiple proteins including Aurora B kinase and INCENP is thought to be responsible for H3 phosphorylation, chromosome condensation and the subsequent segregation of chromosomes. In this report, we show that chromosomes with DRT/DMC contain phosphorylated Chk1, consistent with activation of the S–M phase checkpoint. Furthermore, we show that INCENP is recruited to the DRT/DMC chromosomes during all phases of mitosis. In contrast, Aurora B kinase is absent on DRT/DMC chromosomes when these chromosomes lack serine 10 phosphorylation of H3. We also show that mitotic arrest deficient 2 (Mad2), a member of the spindle assembly checkpoint, is present on DRT/DMC chromosomes at a time when the normally condensed chromosomes show no Mad2 staining, indicating that DRT/DMC activates the spindle assembly checkpoint. Finally, cells with DRT/DMC chromosomes have centrosome amplification, abnormal spindle assembly, endoreduplication and significant chromosome instability.

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Acknowledgements

This work was supported by the National Institutes of Health NIH/NIGMS F32-GM071176-01A1 (BHC), The Laura and Greg Norman National Childhood Cancer Foundation (BHC), NCI CA104693 (MT) and NCI CA97021 (MT).

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Authors and Affiliations

  1. Division of Pediatric Hematology and Oncology, Department of Pediatrics, Oregon Health & Science University, Portland, OR, USA

    B H Chang

  2. Department of Biochemistry, Oregon Health & Science University, Portland, OR, USA

    L Smith & M Thayer

  3. Department of Medicine, Oregon Health & Science University, Portland, OR, USA

    J Huang

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  1. B H Chang
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  2. L Smith
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  3. J Huang
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  4. M Thayer
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Correspondence to M Thayer.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Chang, B., Smith, L., Huang, J. et al. Chromosomes with delayed replication timing lead to checkpoint activation, delayed recruitment of Aurora B and chromosome instability. Oncogene 26, 1852–1861 (2007). https://doi.org/10.1038/sj.onc.1209995

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