Defect in Multiple Cell Cycle Checkpoints in Ataxia-Telangiectasia Postirradiation*
- From the ‡ Queensland Cancer Fund Research Unit, Queensland Institute of Medical Research, Bancroft Centre, 300 Herston Road, Brisbane, Queensland 4029, Australia and the
- § Department of Surgery, University of Queensland, Royal Brisbane Hospital, Herston, Queensland 4029, Australia
- ¶ To whom correspondence should be addressed. Tel.: 61-7-3362-0341; Fax: 61-7-3362-0106; E-mail: martinL{at}qimr.edu.au.
Abstract
The recent description of a novel gene (ATM) mutated in ataxia-telangiectasia (A-T), with homologies to genes encoding proteins involved in both G1/S and G2/M checkpoint control, points to a common defect in cell cycle control in A-T operating through the cyclin-dependent kinases. In this report we demonstrate that cyclin-dependent kinases are resistant to inhibition by ionizing radiation exposure in A-T cells, and this appears to be due to insufficient induction of WAF1. Exposure of control lymphoblastoid cells to radiation during S phase and in G2 phase causes a rapid inhibition of cyclin A-Cdk2 and cyclin B-Cdc2 activities, respectively. Irradiation led to a 5-20-fold increase in Cdk-associated WAF1 in these cells, which accounts at least in part for the decrease in cyclin-dependent kinase activity. In contrast, radiation did not inhibit any of the cyclin-dependent kinase activities in S phase or G2 phase in A-T cells at short times after irradiation nor was there any significant change in the level of Cdk-associated WAF1 compared to unirradiated cells. These results are similar to those reported previously for the G1 checkpoint and provide additional evidence for the involvement of ATM at multiple points in cell cycle regulation.
Footnotes
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↵* This work was supported by grants from the National Health and Medical Research Council of Australia, the A-T Children's Project, Boca Raton, Florida, and the National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵1 The abbreviations used are:
- A-T
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ataxia-telangiectasia
- PBS
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phosphate-buffered saline
- Gy
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gray.
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↵2K. K. Khanna, J. Yan, K. Hobson, H. Beamish, K. Spring, D. Watters, Y. Shilok, R. A. Gatti, and M. F. Lavin, submitted for publication.
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- Received October 26, 1995.
- Revision received April 18, 1996.
- © 1996 by The American Society for Biochemistry and Molecular Biology, Inc.
