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Originally published In Press as doi:10.1074/jbc.M300003200 on January 6, 2003

J. Biol. Chem., Vol. 278, Issue 11, 9309-9317, March 14, 2003
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ATP Activates Ataxia-Telangiectasia Mutated (ATM) in Vitro
IMPORTANCE OF AUTOPHOSPHORYLATION*

Sergei KozlovDagger , Nuri GuevenDagger , Katherine Keating§, Jonathan RamsayDagger , and Martin F. LavinDagger ||**

From Dagger  The Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Herston Qld 4029, Australia, § EIRX Therapeutics Ltd., Cork, Airport Business Park, Cork, Ireland, the  Queensland Radium Institute, Mater Hospital, Brisbane Qld 4101, Australia, and the || Department of Surgery, University of Queensland, PO Royal Brisbane Hospital, Herston QLD 4029, Australia

Ataxia-telangiectasia Mutated (ATM), mutated in the human disorder ataxia-telangiectasia, is rapidly activated by DNA double strand breaks. The mechanism of activation remains unresolved, and it is uncertain whether autophosphorylation contributes to activation. We describe an in vitro immunoprecipitation system demonstrating activation of ATM kinase from unirradiated extracts by preincubation with ATP. Activation is both time- and ATP concentration-dependent, other nucleotides fail to activate ATM, and DNA is not required. ATP activation is specific for ATM since it is not observed with kinase-dead ATM, it requires Mn2+, and it is inhibited by wortmannin. Exposure of activated ATM to phosphatase abrogates activity, and repeat cycles of ATP and phosphatase treatment reveal a requirement for autophosphorylation in the activation process. Phosphopeptide mapping revealed similarities between the patterns of autophosphorylation for irradiated and ATP-treated ATM. Caffeine inhibited ATM kinase activity for substrates but did not interfere with ATM autophosphorylation. ATP failed to activate either A-T and rad3-related protein (ATR) or DNA-dependent protein kinase under these conditions, supporting the specificity for ATM. These data demonstrate that ATP can specifically induce activation of ATM by a mechanism involving autophosphorylation. The relationship of this activation to DNA damage activation remains unclear but represents a useful model for understanding in vivo activation.

* This work was supported by grants from the Australian National Health and Medical Research Council, the Queensland Cancer Fund, and the A-T Children's Project, Florida.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.

** To whom correspondence should be addressed: The Queensland Cancer Fund Research Unit, The Queensland Institute of Medical Research, P. O. Box Royal Brisbane Hospital, Herston, Brisbane 4029, Australia. Tel.: 617-3362-0341; Fax: 617-3362-0106; E-mail: martinL@qimr.edu.au.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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