Abstract
Chemicals that target microtubules induce mitotic stress by affecting several processes that occur during mitosis. These processes include separation of the centrosomes in prophase, alignment of the chromosomes on the spindle in metaphase and sister-chromatid separation in anaphase1,2. Many human cancers are sensitive to mitotic stress. This sensitivity is being exploited for therapy and implies checkpoint defects2,3,4,5,6,7,8. The known mitotic checkpoint genes, which prevent entry into anaphase when the chromosomes are not properly aligned on the mitotic spindle, are, however, rarely inactivated in human cancer9,10,11,12,13. Here we describe the chfr gene, which is inactivated owing to lack of expression or by mutation in four out of eight human cancer cell lines examined. Normal primary cells and tumour cell lines that express wild-type chfr exhibited delayed entry into metaphase when centrosome separation was inhibited by mitotic stress. In contrast, the tumour cell lines that had lost chfr function entered metaphase without delay. Ectopic expression of wild-type chfr restored the cell cycle delay and increased the ability of the cells to survive mitotic stress. Thus, chfr defines a checkpoint that delays entry into metaphase in response to mitotic stress.
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Acknowledgements
We thank G. Maul for the gift of autoimmune serum Ab598; A. Janss for advice on cell synchronization; J. Bothos, M. Summers, M. Appel and M. Shayhorn for technical help; M. Scolnick for editing the manuscript; and E. Stavridi, N. Chehab, G. Rovera, F. Rauscher III and P. Leder for comments and advice. We also thank the Wistar Institute's NCI-supported Microscopy, Sequencing and Bioinformatics Facilities for technical help and access to their equipment. D.M.S. is supported by an NCI Training Grant awarded to the Wistar Institute.
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Scolnick, D., Halazonetis, T. Chfr defines a mitotic stress checkpoint that delays entry into metaphase. Nature 406, 430–435 (2000). https://doi.org/10.1038/35019108
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DOI: https://doi.org/10.1038/35019108
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