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  • Original Article
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Depletion of CHK1, but not CHK2, induces chromosomal instability and breaks at common fragile sites

Oncogene volume 25, pages 4381–4388 (2006)Cite this article

Abstract

Common fragile sites are specific regions of the genome that form gaps and breaks on metaphase chromosomes when DNA synthesis is partially inhibited. Fragile sites and their associated genes show frequent deletions and other rearrangements in cancer cells, and may be indicators of DNA replication stress early in tumorigenesis. We have previously shown that the DNA damage response proteins ATR, BRCA1 and FANCD2 play critical roles in maintaining the stability of fragile site regions. To further elucidate the pathways regulating fragile site stability, we have investigated the effects of depletion of the cell cycle checkpoint kinases, CHK1 and CHK2 on common fragile site stability in human cells. We demonstrate that both CHK1 and CHK2 are activated following treatment of cells with low doses of aphidicolin that induce fragile site breakage. Furthermore, we show that depletion of CHK1, but not CHK2, using short-interfering RNA (siRNA) leads to highly destabilized chromosomes and specific common fragile site breakage. In many cells, CHK1 depletion resulted in extensive chromosome fragmentation, which was distinct from endonucleolytic cleavage commonly associated with apoptosis. These findings demonstrate a critical role for the CHK1 kinase in regulating chromosome stability, and in particular, common fragile site stability.

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Acknowledgements

We thank Sara Hamon and Mats Ljungman for technical assistance as well as David Ferguson, Chris Canman, Ryan Ragland, and Susan Dagenais for helpful discussions and thoughtful comments. This study was supported by NIH Grants CA 43222 (TWG) and 5 T32 GMO 7544 (SGD). NGH is the recipient of a Leukemia Research Foundation Postdoctoral Fellowship.

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  1. Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA

    S G Durkin, M F Arlt, N G Howlett & T W Glover

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  1. S G Durkin
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  2. M F Arlt
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  4. T W Glover
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Correspondence to T W Glover.

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

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Durkin, S., Arlt, M., Howlett, N. et al. Depletion of CHK1, but not CHK2, induces chromosomal instability and breaks at common fragile sites. Oncogene 25, 4381–4388 (2006). https://doi.org/10.1038/sj.onc.1209466

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