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Abstract
Mutations in the Artemis protein in humans result in hypersensitivity to DNA double-strand
break-inducing agents and absence of B and T lymphocytes (radiosensitive severe combined
immune deficiency [RS-SCID]). Here, we report that Artemis forms a complex with the
469 kDa DNA-dependent protein kinase (DNA-PKcs) in the absence of DNA. The purified
Artemis protein alone possesses single-strand-specific 5' to 3' exonuclease activity.
Upon complex formation, DNA-PKcs phosphorylates Artemis, and Artemis acquires endonucleolytic
activity on 5' and 3' overhangs, as well as hairpins. Finally, the Artemis:DNA-PKcs
complex can open hairpins generated by the RAG complex. Thus, DNA-PKcs regulates Artemis
by both phosphorylation and complex formation to permit enzymatic activities that
are critical for the hairpin-opening step of V(D)J recombination and for the 5' and
3' overhang processing in nonhomologous DNA end joining.