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J. Biol. Chem., Vol. 280, Issue 15, 15158-15164, April 15, 2005

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DNA Damage-induced Association of ATM with Its Target Proteins Requires a Protein Interaction Domain in the N Terminus of ATM^*

Norvin Fernandes, Yingli Sun, Shujuan Chen, Proma Paul, Reuben J. Shaw, Lewis C. Cantley, and Brendan D. Price¶

From the Department of Radiation Oncology, Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts 02115 and the Department of Systems Biology, Harvard Medical School and Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115

The ATM protein kinase regulates the response of the cell to DNA damage by associating with and then phosphorylating proteins involved in cell cycle checkpoints and DNA repair. Here, we report on deletion studies designed to identify protein domains required for ATM to phosphorylate target proteins and to control cell survival following exposure to ionizing radiation. Deletion studies demonstrated that amino acids 1–150 of ATM were required for the ATM protein to regulate cellular radiosensitivity. Additional deletions and point mutations indicated that this domain extended from amino acids 81–106 of ATM, with amino acid substitutions located between amino acids 91 and 97 inactivating the functional activity of ATM. When ATM with mutations in this region (termed ATM90) was expressed in AT cells, it was unable to restore normal radiosensitivity to the cells. However, ATM90 retained normal kinase activity and was autophosphorylated on serine 1981 following exposure to DNA damage. Furthermore, wild-type ATM displayed DNA-damage induced association with p53, brca1, and LKB1 in vivo, whereas ATM90 failed to form productive complexes with these target proteins either in vivo or in vitro. Furthermore, ATM90 did not phosphorylate p53 in vivo and did not form nuclear foci in response to ionizing radiation. We propose that amino acids 91–97 of ATM contain a protein interaction domain required for the DNA damage-induced association between ATM and its target proteins, including the brca1, p53, and LKB1 proteins. Furthermore, this domain of ATM is required for ATM to form nuclear foci following exposure to ionizing radiation.

Received for publication, October 25, 2004 , and in revised form, December 22, 2004.

^* This work was supported by National Institutes of Health Grants CA64585 and CA93602 (to B. D. P.) and by funds from the Associates of the Joint Center of Radiation Therapy Foundation and the Childrens A-T Project. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom all correspondence should be addressed: JF513, Dana-Farber Cancer Inst., 44 Binney St., Boston, MA 02115. Tel.: 617-632-4946; Fax: 617-632-4599; E-mail: brendan_price{at}dfci.harvard.edu.

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