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Multiple autophosphorylation sites are dispensable for murine ATM activation in vivo

¹ Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
² Department of Public Health and Cellular Biology, University of Tor Vergata, 00175 Rome, Italy
³ Department of Molecular Genetics and Microbiology, Institute of Cellular and Molecular Biology, University of Texas at Austin, Austin, TX 78712
⁴ Science Applications International Corporation–Frederick, National Cancer Institute at Frederick Cancer Research and Development Center, Frederick, MD 21702

Correspondence to André Nussenzweig: andre_nussenzweig{at}nih.gov

Cellular responses to both physiological and pathological DNA double-strand breaks are initiated through activation of the evolutionarily conserved ataxia telangiectasia mutated (ATM) kinase. Upon DNA damage, an activation mechanism involving autophosphorylation has been reported to allow ATM to phosphorylate downstream targets important for cell cycle checkpoints and DNA repair. In humans, serine residues 367, 1893, and 1981 have been shown to be autophosphorylation sites that are individually required for ATM activation. To test the physiological importance of these sites, we generated a transgenic mouse model in which all three conserved ATM serine autophosphorylation sites (S367/1899/1987) have been replaced with alanine. In this study, we show that ATM-dependent responses at both cellular and organismal levels are functional in mice that express a triple serine mutant form of ATM as their sole ATM species. These results lend further support to the notion that ATM autophosphorylation correlates with the DNA damage–induced activation of the kinase but is not required for ATM function in vivo.

Abbreviations used in this paper: ATM, ataxia telangiectasia mutated; BAC, bacterial artificial chromosome; CSR, class switch recombination; DSB, double-strand break; LN, lymph node; LPS, lipopolysaccharide; MRN, MRE11–RAD50–NBS1; PE, phycoerythrin; SP, single positive; TCR, T cell receptor; Tg, transgene; WT, wild type.

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