Artemis plays an essential role in V(D)J recombination, the process by which B cellantibody genes and T cell receptor genes are assembled from individual V (variable), D (diversity), and J (joining) segments.[4] For example, in joining a V segment to a D segment, the RAG (recombination activating gene) nuclease cuts both DNA strands adjacent to a V segment and adjacent to a D segment. The intervening DNA between the V and D segments is ligated to form a circular DNA molecule that is lost from the chromosome. At each of the two remaining ends, called the coding ends, the two strands of DNA are joined to form a hairpin structure. Artemis nuclease, in a complex with the DNA-dependent protein kinase (DNA‑PK), binds to these DNA ends and makes a single cut near the tip of the hairpin. The exposed 3' termini are subject to deletion and addition of nucleotides by a variety of exonucleases and DNA polymerases, before the V and D segments are ligated to restore the integrity of the chromosome. The exact site of cleavage of the hairpin by Artemis is variable, and this variability, combined with random nucleotide deletion and addition, confers extreme diversity upon the resulting antibody and T-cell receptor genes, thus allowing the immune system to mount an immune response to virtually any foreign antigen.[5] In Artemis-deficient individuals, V(D)J recombination is blocked because the hairpin ends cannot be opened, and so no mature B or T cells are produced, a condition known as severe combined immune deficiency (SCID). Artemis was first identified as the gene defective in a subset of SCID patients that were unusually sensitive to radiation.
Cells deficient in Artemis are more sensitive than normal cells to X‑rays[1] and to chemical agents that induce double-strand breaks (DSBs),[6] and they show a higher incidence of chromosome breaks following irradiation.[7] Direct measurement of DSBs by pulsed-field electrophoresis indicates that in Artemis-deficient cells 75-90% of DSBs are repaired rapidly, just as in normal cells. However, the remaining 10-20% of DSBs that are repaired more slowly (2-24 hr) in normal cells, are not repaired at all in Artemis-deficient cells.[8] Repair of these presumably difficult-to-rejoin breaks also requires several other proteins, including the Mre11/Rad50/NBS1 complex, the ataxia telangiectasia-mutated ATM kinase, and 53BP1. Because Artemis can remove damaged ends from DNA,[6] it has been proposed that these DSBs are those whose damaged ends require trimming by Artemis. However, evidence that both ATM and Artemis are specifically required for repair of DSBs in heterochromatin,[9][10] has called this interpretation into question.
↑ 1.01.1Moshous D, Callebaut I, de Chasseval R, Corneo B, Cavazzana-Calvo M, Le Deist F, Tezcan I, Sanal O, Bertrand Y, Philippe N, Fischer A, de Villartay JP (May 2001). "Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency". Cell. 105 (2): 177–86. doi:10.1016/S0092-8674(01)00309-9. PMID11336668.
↑Riballo E, Kühne M, Rief N, Doherty A, Smith GC, Recio MJ, Reis C, Dahm K, Fricke A, Krempler A, Parker AR, Jackson SP, Gennery A, Jeggo PA, Löbrich M (December 2004). "A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to gamma-H2AX foci". Mol. Cell. 16 (5): 715–24. doi:10.1016/j.molcel.2004.10.029. PMID15574327.
↑Goodarzi AA, Noon AT, Deckbar D, Ziv Y, Shiloh Y, Löbrich M, Jeggo PA (July 2008). "ATM signaling facilitates repair of DNA double-strand breaks associated with heterochromatin". Mol. Cell. 31 (2): 167–77. doi:10.1016/j.molcel.2008.05.017. PMID18657500.
↑Ma Y, Pannicke U, Schwarz K, Lieber MR (March 2002). "Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination". Cell. 108 (6): 781–94. doi:10.1016/S0092-8674(02)00671-2. PMID11955432.
Ma Y, Pannicke U, Schwarz K, Lieber MR (2002). "Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination". Cell. 108 (6): 781–94. doi:10.1016/S0092-8674(02)00671-2. PMID11955432.
Li L, Moshous D, Zhou Y, Wang J, Xie G, Salido E, Hu D, de Villartay JP, Cowan MJ (2002). "A founder mutation in Artemis, an SNM1-like protein, causes SCID in Athabascan-speaking Native Americans". J. Immunol. 168 (12): 6323–9. doi:10.4049/jimmunol.168.12.6323. PMID12055248.
Noordzij JG, Verkaik NS, van der Burg M, van Veelen LR, de Bruin-Versteeg S, Wiegant W, Vossen JM, Weemaes CM, de Groot R, Zdzienicka MZ, van Gent DC, van Dongen JJ (2003). "Radiosensitive SCID patients with Artemis gene mutations show a complete B-cell differentiation arrest at the pre-B-cell receptor checkpoint in bone marrow". Blood. 101 (4): 1446–52. doi:10.1182/blood-2002-01-0187. PMID12406895.
Kobayashi N, Agematsu K, Sugita K, Sako M, Nonoyama S, Yachie A, Kumaki S, Tsuchiya S, Ochs HD, Sugita K, Fukushima Y, Komiyama A (2003). "Novel Artemis gene mutations of radiosensitive severe combined immunodeficiency in Japanese families". Hum. Genet. 112 (4): 348–52. doi:10.1007/s00439-002-0897-x. PMID12592555.
Kobayashi N, Agematsu K, Nagumo H, Yasui K, Katsuyama Y, Yoshizawa K, Ota M, Yachie A, Komiyama A (2003). "Expansion of clonotype-restricted HLA-identical maternal CD4+ T cells in a patient with severe combined immunodeficiency and a homozygous mutation in the Artemis gene". Clin. Immunol. 108 (2): 159–66. doi:10.1016/S1521-6616(03)00095-0. PMID12921762.
Poinsignon C, de Chasseval R, Soubeyrand S, Moshous D, Fischer A, Haché RJ, de Villartay JP (2004). "Phosphorylation of Artemis following irradiation-induced DNA damage". Eur. J. Immunol. 34 (11): 3146–55. doi:10.1002/eji.200425455. PMID15468306.
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