DCLRE1C encodes Artemis, a nuclease essential for DNA repair and adaptive immunity. Artemis functions as a 5'-3' exonuclease that acquires endonucleolytic activity when complexed with DNA-PKcs (DNA-PK) 1. Its primary role is resolving hairpin DNA ends generated during V(D)J recombination, the process assembling immunoglobulin and T-cell receptor genes 1. Artemis also participates in nonhomologous end joining (NHEJ) repair of ionizing radiation-induced double-strand breaks requiring substantial end-processing 1. DNA-PK regulates Artemis recruitment and activation at DNA ends through autophosphorylation 1. DCLRE1C mutations cause Artemis-deficient severe combined immunodeficiency (ART-SCID), characterized by absent T and B cells, radiosensitivity, and opportunistic infections 2. Hypomorphic mutations produce leaky SCID with variable presentations including recurrent infections, autoimmunity, and malignancy 3. Gene therapy using lentiviral-transduced autologous CD34+ cells successfully reconstituted T and B cell immunity in ART-SCID infants, with sustained immune function at 24+ months follow-up 2. Mutation functional analysis reveals correlation between residual Artemis activity levels and clinical severity, with compound heterozygous genotypes often causing leaky rather than typical SCID 4.