1. ^† Joint Center for Radiation Therapy and Division of Cancer Pharmacology, Dana-Farber Cancer Institutes, Boston, Massachusetts 02115, USA
2. ^‡,  The Queensland Institute of Medical Research, and^¶Department of Surgery, University of Queensland, Royal Brisbane Hospital, Herston, Brisbane, Queensland 4029, Australia
3. ^§Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
4. Department of Human Genetics, Sackler School of Medicine, Tel Aviv University, RamatAviv, 69978, Israel
5. ^* K.K.K, and TS. contributed equally to this work.

Abstract

The gene mutated in the autosomal recessive disorder ataxia telangiectasia (AT), designated ATM (for 'AT mutated'), is a member of a family of phosphatidylinositol-3-kinase-like enzymes that are involved in cell-cycle control, meiotic recombination, telomere length monitoring and DNA-damage response^1–4. Previous results have demonstrated that AT cells are hypersensitive to ionizing radiation^5–7 and are defective at the Gl/S checkpoint after radiation damage^8–10. Because cells lacking the protein tyrosine kinase c-Abl are also defective in radiation-induced Gl arrest¹¹, we investigated the possibility that ATM might interact with c-Abl in response to radiation damage. Here we show that ATM binds c-Abl constitutively in control cells but not in AT cells. Our results demonstrate that the SH3 domain of c-Abl interacts with a DPAPNPPHFP motif (residues 1,373–1,382) of ATM. The results also reveal that radiation-induction of c-Abl tyrosine kinase activity is diminished in AT cells. These findings indicate that ATM is involved in the activation of c-Abl by DNA damage and this interaction may in part mediate radiation-induced Gl arrest.