the rearrangement process through the recognition of and Jean-Pierre de Villartay* the RSS and the introduction of a DNA double-strand * De ´veloppement Normal et Pathologique break (dsb) at the border of the heptamer (Schatz et du Syste me Immunitaire al., 1989; Oettinger et al., 1990). The subsequent step INSERM U429 consists of recognition and signaling of the DNA damage Ho ˆpital Necker Enfants Malades to the ubiquitously expressed DNA repair machinery. 149 rue de Se vres The description of the murine scid anomaly, character-75015 Paris ized by a lack of circulating mature B and T lymphocytes France (Bosma et al., 1983), as a general DNA repair defect † LMCP, CNRS UMR C7590 accompanied by an increased sensitivity to ionizing ra-Universite ´s Paris 6 et Paris 7 diation or other agents causing DNA dsb, provided the Paris 75005 link between V(D)J recombination and DNA dsb repair France (Fulop and Phillips, 1990; Biedermann et al., 1991; Hen- ‡ Immunology Division drickson et al., 1991). This was further confirmed by Hacettepe University the analysis of Chinese ovary cell lines (CHO), initially Ihsan Dogramaci Children's Hospital selected on the basis of their defect in DNA repair (Tacci-Ankara, Turkey oli et al., 1993). This led to the description of the Ku70/ § He ´matologie Pe ´diatrique Ku80/DNA-PKcs complex as a DNA damage sensor (re-Ho ˆpital Debrousse viewed in Jackson and Jeggo, 1995). Briefly, DNA-PKcs Lyon, France is a DNA-dependent protein kinase that belongs to the phosphoinositol (PI) kinase family, which is recruited at the site of the DNA lesion through the interaction with Summary the regulatory complex Ku70/80 that binds to DNA ends (Gottlieb and Jackson, 1993). Cells from scid mice lack The V(D)J recombination process insures the somatic DNA-PK activity owing to a mutation in the DNA-PKcs diversification of immunoglobulin and antigen T cell encoding gene (Blunt et al., 1996; Danska et al., 1996). receptor encoding genes. This reaction is initiated by In the final phase of the V(D)J rearrangement, the DNA a DNA double-strand break (dsb), which is resolved repair machinery per se will ensure the re-ligation of the by the ubiquitously expressed DNA repair machinery. two chromosomal broken ends. This last step resembles Human T-B-severe combined immunodeficiency asthe well-known DNA nonhomologous end joining (NHEJ) sociated with increased cellular radiosensitivity (RSpathway in the yeast Saccharomyces cerevisiae (re-SCID) is characterized by a defect in the V(D)J recomviewed in Haber, 2000). It involves the XRCC4 (Li et al., bination leading to an early arrest of both B and T 1995) and the DNA ligaseIV (Robins and Lindahl, 1996) cell maturation. We previously mapped the diseasefactors. V(D)J recombination represents a critical checkrelated locus to the short arm of chromosome 10. We point in the development of the immune system. Indeed, herein describe the cloning of the gene encoding a all the animal models carrying a defective gene of either novel protein involved in V(D)J recombination/DNA reone of the known V(D)J recombination factors, either pair, Artemis, whose mutations cause human RSnatural (murine and equine scid) or engineered through SCID. Protein sequence analysis strongly suggests homologous recombination, exhibit a profound defect that Artemis belongs to the metallo--lactamase suin the lymphoid developmental program owing to an perfamily. arrest of the B and T cell maturation at early stages (Mombaerts et al., 1992; Shinkai et al., 1992; Nussen-