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¹ Développement Normal et Pathologique du Système Immunitaire, INSERM U429, Hôpital Necker Enfants Malades, 75015 Paris, France
² Systèmes Moléculaires et Biologie Structurale, CNRS UMR7590, Universités Paris 6 et Paris 7, 75005 Paris, France

Address correspondence to Jean-Pierre de Villartay, INSERM U429, Hôpital Necker, 149 Rue de Sèvres, 75015 Paris, France. Phone: 33-1-44-49-50-81; Fax: 33-1-42-73-06-40; email: devillar{at}necker.fr

The V(D)J recombination/DNA repair factor Artemis belongs to the metallo-ß-lactamase (ß-Lact) superfamily of enzymes. Three regions can be defined within the Artemis protein sequence: (a) the ß-Lact homology domain, to which is appended (b) the ß-CASP region, specific of members of the ß-Lact superfamily acting on nucleic acids, and (c) the COOH-terminal domain. Using in vitro mutagenesis, here we show that the association of the ß-Lact and the ß-CASP regions suffices for in vivo V(D)J recombination of chromosome-integrated substrates. Single amino acid mutants point to critical catalytic residues for V(D)J recombination activity. The results presented here define the ß-Lact/ß-CASP domain of Artemis as the minimal core catalytic domain needed for V(D)J recombination and suggest that Artemis uses one or two Zn(II) ions to exert its catalytic activity, like bacterial class B ß-Lact enzymes hydrolyzing ß-lactam compounds.

Key Words: Artemis • metallo-ß-lactamases • ß-CASP • V(D)J recombination • DNA repair

Abbreviations used in this paper: ß-Lact, metallo-ß-lactamase; CE, coding ends; DNA-dsb, DNA double strand break; DNA-PKcs, DNA-dependent protein kinase catalytic subunit; EGFP, enhanced green fluorescent protein; FL, full-length; GFP, green fluorescent protein; GST, glutathione-S-transferase; RS-SCID, radiosensitive SCID; RSS, recombination signal sequences; WB, Western blotting.

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