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Impact of G2 checkpoint defect on centromeric instability

Oncogene volume 30, pages 1281–1289 (2011)Cite this article

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Abstract

Centromeric instability is characterized by dynamic formation of centromeric breaks, deletions, isochromosomes and translocations, which are commonly observed in cancer. So far, however, the mechanisms of centromeric instability in cancer cells are still poorly understood. In this study, we tested the hypothesis that G2 checkpoint defect promotes centromeric instability. Our observations from multiple approaches consistently support this hypothesis. We found that overexpression of cyclin B1, one of the pivotal genes driving G2 to M phase transition, impaired G2 checkpoint and promoted the formation of centromeric aberrations in telomerase-immortalized cell lines. Conversely, centromeric instability in cancer cells was ameliorated through reinforcement of G2 checkpoint by cyclin B1 knockdown. Remarkably, treatment with KU55933 for only 2.5 h, which abrogated G2 checkpoint, was sufficient to produce centromeric aberrations. Moreover, centromeric aberrations constituted the major form of structural abnormalities in G2 checkpoint-defective ataxia telangiectasia cells. Statistical analysis showed that the frequencies of centromeric aberrations in G2 checkpoint-defective cells were always significantly overrepresented compared with random assumption. As there are multiple pathways leading to G2 checkpoint defect, our finding offers a broad explanation for the common occurrence of centromeric aberrations in cancer cells.

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Acknowledgements

We thank Dr Prochownik, Children's Hospital of Pittsburgh, Pittsburgh, PA, for the kind gift of pApuro-CyclinB1 plasmids, and Department of Pediatrics and Adolescent Medicine, The University of Hong Kong for use of SKY facilities. We also thank Dr JC Tang (Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University) and Professor G Srivastava (Department of Pathology, The University of Hong Kong) for the SLMT-1 cell line, and Dr R Glaser (Department of Medical Microbiology and Immunology, Ohio State University Medical Center) for the HNE-1 cell line; T Chan, PY Cheung, CS Leung, P Mak, J Cheung, A Li and B Lai for technical assistance. This study was supported by a grant from the Research Grants Council of Hong Kong Special Administrative Region, China, Project No. HKU 7556/06M.

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  1. Department of Anatomy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China

    W Deng, S W Tsao, G W Y Mak, C M Tsang, Y P Ching, M S Y Huen & A L M Cheung

  2. Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, SAR, China

    X -Y Guan

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Correspondence to A L M Cheung.

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Deng, W., Tsao, S., Mak, G. et al. Impact of G2 checkpoint defect on centromeric instability. Oncogene 30, 1281–1289 (2011). https://doi.org/10.1038/onc.2010.508

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