Artemis (protein) explained

Artemis is a protein that in humans is encoded by the DCLRE1C (DNA cross-link repair 1C) gene.^{[1] [2]}

Function

Artemis is a nuclear protein that is involved in V(D)J recombination and DNA repair. The protein has endonuclease activity on 5' and 3' overhangs and hairpins when complexed with PRKDC.^[3]

Immune response

Artemis plays an essential role in V(D)J recombination, the process by which B cell antibody 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.

Repair of DNA breaks

Cells deficient in Artemis are more sensitive than normal cells to X‑rays 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.

Artemis functions in the repair of DNA double-strand breaks that arise by induced oxidative reactions, or by endogenous reactions.^[11] Such DNA repair occurs in heterochromatin as well as in euchromatin.

Clinical significance

Mutations in this gene cause Athabascan-type severe combined immunodeficiency (SCIDA).^[12]

Interactions

DCLRE1C has been shown to interact with DNA-PKcs.^[13]

Further reading

• Dudásová Z, Chovanec M . Artemis, a novel guardian of the genome . Neoplasma . 50 . 5 . 311–8 . 2003 . 14628082 .
• Adams MD, Kerlavage AR, Fleischmann RD, Fuldner RA, Bult CJ, Lee NH, Kirkness EF, Weinstock KG, Gocayne JD, White O . Initial assessment of human gene diversity and expression patterns based upon 83 million nucleotides of cDNA sequence . Nature . 377 . 6547 Suppl . 3–174 . 1995 . 7566098 . .
• Wood RD, Mitchell M, Sgouros J, Lindahl T . Human DNA repair genes . Science . 291 . 5507 . 1284–9 . 2001 . 11181991 . 10.1126/science.1056154 . 2001Sci...291.1284W . 17375001 .
• Ma Y, Pannicke U, Schwarz K, Lieber MR . 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 . 2002 . 11955432 . 10.1016/S0092-8674(02)00671-2 . 7575525 . free .
• Li L, Moshous D, Zhou Y, Wang J, Xie G, Salido E, Hu D, de Villartay JP, Cowan MJ . A founder mutation in Artemis, an SNM1-like protein, causes SCID in Athabascan-speaking Native Americans . J. Immunol. . 168 . 12 . 6323–9 . 2002 . 12055248 . 10.4049/jimmunol.168.12.6323 . free .
• Callebaut I, Moshous D, Mornon JP, de Villartay JP . Metallo-beta-lactamase fold within nucleic acids processing enzymes: the beta-CASP family . Nucleic Acids Res. . 30 . 16 . 3592–601 . 2002 . 12177301 . 134238 . 10.1093/nar/gkf470 .
• 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 . 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 . 2003 . 12406895 . 10.1182/blood-2002-01-0187 . free . 1765/8235 . free .
• Moshous D, Pannetier C, de Chasseval R, le Deist F, Cavazzana-Calvo M, Romana S, Macintyre E, Canioni D, Brousse N, Fischer A, Casanova JL, de Villartay JP . Partial T and B lymphocyte immunodeficiency and predisposition to lymphoma in patients with hypomorphic mutations in Artemis . J. Clin. Invest. . 111 . 3 . 381–7 . 2003 . 12569164 . 151863 . 10.1172/JCI16774 .
• Kobayashi N, Agematsu K, Sugita K, Sako M, Nonoyama S, Yachie A, Kumaki S, Tsuchiya S, Ochs HD, Sugita K, Fukushima Y, Komiyama A . Novel Artemis gene mutations of radiosensitive severe combined immunodeficiency in Japanese families . Hum. Genet. . 112 . 4 . 348–52 . 2003 . 12592555 . 10.1007/s00439-002-0897-x . 11582061 .
• Kobayashi N, Agematsu K, Nagumo H, Yasui K, Katsuyama Y, Yoshizawa K, Ota M, Yachie A, Komiyama A . 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 . 2003 . 12921762 . 10.1016/S1521-6616(03)00095-0 .
• Poinsignon C, Moshous D, Callebaut I, de Chasseval R, Villey I, de Villartay JP . The metallo-beta-lactamase/beta-CASP domain of Artemis constitutes the catalytic core for V(D)J recombination . J. Exp. Med. . 199 . 3 . 315–21 . 2004 . 14744996 . 2211804 . 10.1084/jem.20031142 .
• Pannicke U, Ma Y, Hopfner KP, Niewolik D, Lieber MR, Schwarz K . Functional and biochemical dissection of the structure-specific nuclease ARTEMIS . EMBO J. . 23 . 9 . 1987–97 . 2004 . 15071507 . 404326 . 10.1038/sj.emboj.7600206 .
• Zhang X, Succi J, Feng Z, Prithivirajsingh S, Story MD, Legerski RJ . Artemis is a phosphorylation target of ATM and ATR and is involved in the G2/M DNA damage checkpoint response . Mol. Cell. Biol. . 24 . 20 . 9207–20 . 2004 . 15456891 . 517881 . 10.1128/MCB.24.20.9207-9220.2004 .
• Poinsignon C, de Chasseval R, Soubeyrand S, Moshous D, Fischer A, Haché RJ, de Villartay JP . Phosphorylation of Artemis following irradiation-induced DNA damage . Eur. J. Immunol. . 34 . 11 . 3146–55 . 2004 . 15468306 . 10.1002/eji.200425455 . free .

Notes and References

1. Moshous 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 . 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 . May 2001 . 11336668 . 10.1016/S0092-8674(01)00309-9 . 12610896 . 11655/13789 . free .
2. Li L, Drayna D, Hu D, Hayward A, Gahagan S, Pabst H, Cowan MJ . The gene for severe combined immunodeficiency disease in Athabascan-speaking Native Americans is located on chromosome 10p . Am. J. Hum. Genet. . 62 . 1 . 136–44 . Mar 1998 . 9443881 . 1376812 . 10.1086/301688 .
3. Web site: Protein Knowledgebase: Gene DCLRE1C - DNA cross-link repair 1C protein (Protein artemis). June 2, 2011.
4. Book: de Villartay JP . V(D)J recombination deficiencies . 650 . 46–58 . 2009 . 19731800 . 10.1007/978-1-4419-0296-2_4 . Advances in Experimental Medicine and Biology . 978-1-4419-0295-5 .
5. Lu H, Schwarz K, Lieber MR . Extent to which hairpin opening by the Artemis:DNA-PKcs complex can contribute to junctional diversity in V(D)J recombination . Nucleic Acids Res. . 35 . 20 . 6917–23 . 2007 . 17932067 . 2175297 . 10.1093/nar/gkm823 .
6. Povirk LF, Zhou T, Zhou R, Cowan MJ, Yannone SM . Processing of 3'-phosphoglycolate-terminated DNA double strand breaks by Artemis nuclease . J. Biol. Chem. . 282 . 6 . 3547–58 . February 2007 . 17121861 . 10.1074/jbc.M607745200 . free .
7. Deckbar D, Birraux J, Krempler A, Tchouandong L, Beucher A, Walker S, Stiff T, Jeggo P, Löbrich M . Chromosome breakage after G2 checkpoint release . J. Cell Biol. . 176 . 6 . 749–55 . March 2007 . 17353355 . 2064048 . 10.1083/jcb.200612047 .
8. 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 . A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to gamma-H2AX foci . Mol. Cell . 16 . 5 . 715–24 . December 2004 . 15574327 . 10.1016/j.molcel.2004.10.029 . free .
9. Goodarzi AA, Noon AT, Deckbar D, Ziv Y, Shiloh Y, Löbrich M, Jeggo PA . ATM signaling facilitates repair of DNA double-strand breaks associated with heterochromatin . Mol. Cell . 31 . 2 . 167–77 . July 2008 . 18657500 . 10.1016/j.molcel.2008.05.017 . free .
10. Beucher A, Birraux J, Tchouandong L, Barton O, Shibata A, Conrad S, Goodarzi AA, Krempler A, Jeggo PA, Löbrich M . ATM and Artemis promote homologous recombination of radiation-induced DNA double-strand breaks in G2 . EMBO J. . 28 . 21 . 3413–27 . November 2009 . 19779458 . 2752027 . 10.1038/emboj.2009.276 .
11. Woodbine L, Brunton H, Goodarzi AA, Shibata A, Jeggo PA . Endogenously induced DNA double strand breaks arise in heterochromatic DNA regions and require ataxia telangiectasia mutated and Artemis for their repair . Nucleic Acids Res. . 39 . 16 . 6986–97 . 2011 . 21596788 . 3167608 . 10.1093/nar/gkr331 .
12. Web site: Entrez Gene: DCLRE1C DNA cross-link repair 1C (PSO2 homolog, S. cerevisiae).
13. Ma Y, Pannicke U, Schwarz K, Lieber MR . 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 . March 2002 . 11955432 . 10.1016/S0092-8674(02)00671-2 . 7575525 . free .