1. Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892-1360, USA
2. Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA
3. SAIC-Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702, USA
4. *These authors contributed equally to this work

Correspondence to: André Nussenzweig¹ Correspondence and requests for materials should be addressed to A.N. (Email: andre_nussenzweig@nih.gov).

Abstract

The ATM (ataxia telangiectasia mutated) protein kinase is activated under physiological and pathological conditions that induce DNA double-strand breaks (DSBs). Loss of ATM or failure of its activation in humans and mice lead to defective cellular responses to DSBs, such as cell cycle checkpoints, radiation sensitivity, immune dysfunction, infertility and cancer predisposition. A widely used biological marker to identify the active form of ATM is the autophosphorylation of ATM at a single, conserved serine residue (Ser 1981 in humans; Ser 1987 in mouse)¹. Here we show that Atm-dependent responses are functional at the organismal and cellular level in mice that express a mutant form of Atm (mutation of Ser to Ala at position 1987) as their sole Atm species. Moreover, the mutant protein does not exhibit dominant-negative interfering activity when expressed physiologically or overexpressed in the context of Atm heterozygous mice. These results suggest an alternative mode for stimulation of Atm by DSBs in which Atm autophosphorylation at Ser 1987, like trans-phosphorylation of downstream substrates, is a consequence rather than a cause of Atm activation.

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