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Molecular and Cellular Biology, September 1999, p. 6076-6084, Vol. 19, No. 9
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Cleavage and Inactivation of ATM during Apoptosis

Graeme C. M. Smith, Fabrizio d'adda di Fagagna, Nicholas D. Lakin, and Stephen P. Jackson*

Wellcome/CRC Institute and Department of Zoology, University of Cambridge, Cambridge, United Kingdom

Received 21 December 1998/Returned for modification 17 February 1999/Accepted 16 June 1999

The activation of the cysteine proteases with aspartate specificity, termed caspases, is of fundamental importance for the execution of programmed cell death. These proteases are highly specific in their action and activate or inhibit a variety of key protein molecules in the cell. Here, we study the effect of apoptosis on the integrity of two proteins that have critical roles in DNA damage signalling, cell cycle checkpoint controls, and genome maintenance---the product of the gene defective in ataxia telangiectasia, ATM, and the related protein ATR. We find that ATM but not ATR is specifically cleaved in cells induced to undergo apoptosis by a variety of stimuli. We establish that ATM cleavage in vivo is dependent on caspases, reveal that ATM is an efficient substrate for caspase 3 but not caspase 6 in vitro, and show that the in vitro caspase 3 cleavage pattern mirrors that in cells undergoing apoptosis. Strikingly, apoptotic cleavage of ATM in vivo abrogates its protein kinase activity against p53 but has no apparent effect on the DNA binding properties of ATM. These data suggest that the cleavage of ATM during apoptosis generates a kinase-inactive protein that acts, through its DNA binding ability, in a trans-dominant-negative fashion to prevent DNA repair and DNA damage signalling.

* Corresponding author. Mailing address: Wellcome/CRC Institute, Tennis Court Rd., Cambridge CB2 1QR, United Kingdom. Phone: 01223 334102. Fax: 01223 334089. E-mail: spj13{at}mole.bio.cam.ac.uk.

Molecular and Cellular Biology, September 1999, p. 6076-6084, Vol. 19, No. 9
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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