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Gene Review

DCLRE1C  -  DNA cross-link repair 1C

Homo sapiens

Synonyms: A-SCID, ARTEMIS, ASCID, DCLREC1C, DNA cross-link repair 1C protein, ...
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Disease relevance of DCLRE1C

  • Here we show that Artemis-deficient cells from Athabascan-speaking Native American SCID patients (SCIDA) display significantly elevated sensitivity to ionizing radiation (IR) but only a very subtle defect in DNA double-strand (DSB) break repair in contrast to the severe DSB repair defect of NHEJ-deficient cells [1].
  • 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]) [2].
  • Partial T and B lymphocyte immunodeficiency and predisposition to lymphoma in patients with hypomorphic mutations in Artemis [3].
  • A computerized system called ARTEMIS has been taking part in the management of a referral hypertension clinic since September 1975 [4].
  • As part of the Artemis project, 11500 isolates (3000 from patients with respiratory tract infections) were collected throughout six European countries between 1994 and 1996 [5].

High impact information on DCLRE1C

  • The products of three of the genes--IL-2RG, Jak3, and IL-7R alpha--are components of cytokine receptors, and the products of three more-RAG1, RAG2, and Artemis-are essential for effecting antigen receptor gene rearrangement [6].
  • 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 [2].
  • The purified Artemis protein alone possesses single-strand-specific 5' to 3' exonuclease activity [2].
  • When complexed with the catalytic subunit of DNA-dependent protein kinase (DNA-PK(cs)), the recently discovered dsDNA break repair protein named Artemis acquires the ability to open hairpin DNA molecules in vitro [7].
  • We herein describe the cloning of the gene encoding a novel protein involved in V(D)J recombination/DNA repair, Artemis, whose mutations cause human RS-SCID [8].

Chemical compound and disease context of DCLRE1C


Biological context of DCLRE1C


Anatomical context of DCLRE1C

  • In vivo studies of Artemis lacking the C-terminal domain have been reported to be sufficient to complement V(D)J recombination in Artemis null cells [11].
  • During V(D)J recombination, Artemis participates in the resolution of hairpin-sealed coding ends, a step crucial to the constitution of the gene encoding for the antigen receptor of lymphocytes [12].
  • Here we show that Artemis is constitutively phosphorylated in cultured cells and undergoes additional phosphorylation events after irradiation [12].
  • Primary human SCIDA fibroblasts accumulate and exhibit persistent arrest at both the G1/S and G2/M boundaries in response to IR, consistent with the presence of persistent DNA damage [1].
  • Radiosensitive SCID patients with Artemis gene mutations show a complete B-cell differentiation arrest at the pre-B-cell receptor checkpoint in bone marrow [14].

Associations of DCLRE1C with chemical compounds

  • After induction of DSBs with modified ends by a high dose of calicheamicin gamma1, Artemis was phosphorylated by DNA PK [15].
  • The results presented here define the beta-Lact/beta-CASP domain of Artemis as the minimal core catalytic domain needed for V(D)J recombination and suggest that Artemis uses one or two Zn(II) ions to exert its catalytic activity, like bacterial class B beta-Lact enzymes hydrolyzing beta-lactam compounds [16].
  • To characterize amino acids essential for its catalytic activities, we mutated nine evolutionary conserved histidine and aspartic acid residues within ARTEMIS [17].
  • Here, we show that Artemis phosphorylation by ATM and DNA-PK in vitro is primarily attributable to S503, S516 and S645 and demonstrate ATM dependent phosphorylation at serine 645 in vivo [18].
  • However, regardless of its association with DNA-PKcs, phosphorylation of Artemis at both S516 and S645 was stimulated in response to the double-stranded DNA-damaging agent bleomycin, albeit to a lesser extent [19].

Physical interactions of DCLRE1C

  • Here, we report that Artemis forms a complex with the 469 kDa DNA-dependent protein kinase (DNA-PKcs) in the absence of DNA [2].

Enzymatic interactions of DCLRE1C

  • Artemis protein is phosphorylated in a PI3-like kinase-dependent manner after either IR or a number of other DNA damaging treatments including etoposide, but SCIDA cells are not hypersensitive to treatment with etoposide [1].
  • Upon complex formation, DNA-PKcs phosphorylates Artemis, and Artemis acquires endonucleolytic activity on 5' and 3' overhangs, as well as hairpins [2].

Regulatory relationships of DCLRE1C


Other interactions of DCLRE1C


Analytical, diagnostic and therapeutic context of DCLRE1C


  1. Artemis deficiency confers a DNA double-strand break repair defect and Artemis phosphorylation status is altered by DNA damage and cell cycle progression. Wang, J., Pluth, J.M., Cooper, P.K., Cowan, M.J., Chen, D.J., Yannone, S.M. DNA Repair (Amst.) (2005) [Pubmed]
  2. Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination. Ma, Y., Pannicke, U., Schwarz, K., Lieber, M.R. Cell (2002) [Pubmed]
  3. Partial T and B lymphocyte immunodeficiency and predisposition to lymphoma in patients with hypomorphic mutations in Artemis. Moshous, D., Pannetier, C., Chasseval Rd, R., Deist Fl, F., Cavazzana-Calvo, M., Romana, S., Macintyre, E., Canioni, D., Brousse, N., Fischer, A., Casanova, J.L., Villartay, J.P. J. Clin. Invest. (2003) [Pubmed]
  4. Hypertension management: the computer as a participant. Degoulet, P., Menard, J., Berger, C., Plouin, P.F., Devries, C., Hirel, J.C. Am. J. Med. (1980) [Pubmed]
  5. Susceptibility of European respiratory tract isolates to trovafloxacin, ciprofloxacin, clarithromycin, azithromycin and ampicillin. Pontani, D., Washton, H., Bouchillon, S., Johnson, J. Eur. J. Clin. Microbiol. Infect. Dis. (1998) [Pubmed]
  6. Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution. Buckley, R.H. Annu. Rev. Immunol. (2004) [Pubmed]
  7. Does artemis end the hunt for the hairpin-opening activity in V(D)J recombination? Schlissel, M.S. Cell (2002) [Pubmed]
  8. Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency. 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, J.P. Cell (2001) [Pubmed]
  9. Processing of 3'-Phosphoglycolate-terminated DNA Double Strand Breaks by Artemis Nuclease. Povirk, L.F., Zhou, T., Zhou, R., Cowan, M.J., Yannone, S.M. J. Biol. Chem. (2007) [Pubmed]
  10. A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to gamma-H2AX foci. Riballo, E., Kühne, M., Rief, N., Doherty, A., Smith, G.C., Recio, M.J., Reis, C., Dahm, K., Fricke, A., Krempler, A., Parker, A.R., Jackson, S.P., Gennery, A., Jeggo, P.A., Löbrich, M. Mol. Cell (2004) [Pubmed]
  11. The DNA-dependent protein kinase catalytic subunit phosphorylation sites in human Artemis. Ma, Y., Pannicke, U., Lu, H., Niewolik, D., Schwarz, K., Lieber, M.R. J. Biol. Chem. (2005) [Pubmed]
  12. Phosphorylation of Artemis following irradiation-induced DNA damage. Poinsignon, C., de Chasseval, R., Soubeyrand, S., Moshous, D., Fischer, A., Haché, R.J., de Villartay, J.P. Eur. J. Immunol. (2004) [Pubmed]
  13. Ataxia-telangiectasia-mutated dependent phosphorylation of Artemis in response to DNA damage. Chen, L., Morio, T., Minegishi, Y., Nakada, S., Nagasawa, M., Komatsu, K., Chessa, L., Villa, A., Lecis, D., Delia, D., Mizutani, S. Cancer Sci. (2005) [Pubmed]
  14. Radiosensitive SCID patients with Artemis gene mutations show a complete B-cell differentiation arrest at the pre-B-cell receptor checkpoint in bone marrow. Noordzij, J.G., Verkaik, N.S., van der Burg, M., van Veelen, L.R., de Bruin-Versteeg, S., Wiegant, W., Vossen, J.M., Weemaes, C.M., de Groot, R., Zdzienicka, M.Z., van Gent, D.C., van Dongen, J.J. Blood (2003) [Pubmed]
  15. Functions and regulation of human artemis in double strand break repair. Dahm, K. J. Cell. Biochem. (2007) [Pubmed]
  16. The metallo-beta-lactamase/beta-CASP domain of Artemis constitutes the catalytic core for V(D)J recombination. Poinsignon, C., Moshous, D., Callebaut, I., de Chasseval, R., Villey, I., de Villartay, J.P. J. Exp. Med. (2004) [Pubmed]
  17. Functional and biochemical dissection of the structure-specific nuclease ARTEMIS. Pannicke, U., Ma, Y., Hopfner, K.P., Niewolik, D., Lieber, M.R., Schwarz, K. EMBO J. (2004) [Pubmed]
  18. DNA-PK autophosphorylation facilitates Artemis endonuclease activity. Goodarzi, A.A., Yu, Y., Riballo, E., Douglas, P., Walker, S.A., Ye, R., Härer, C., Marchetti, C., Morrice, N., Jeggo, P.A., Lees-Miller, S.P. EMBO J. (2006) [Pubmed]
  19. Artemis Phosphorylated by DNA-dependent Protein Kinase Associates Preferentially with Discrete Regions of Chromatin. Soubeyrand, S., Pope, L., De Chasseval, R., Gosselin, D., Dong, F., de Villartay, J.P., Haché, R.J. J. Mol. Biol. (2006) [Pubmed]
  20. Artemis links ATM to G2/M checkpoint recovery via regulation of Cdk1-cyclin B. Geng, L., Zhang, X., Zheng, S., Legerski, R.J. Mol. Cell. Biol. (2007) [Pubmed]
  21. A gene expression restriction network mediated by sense and antisense Alu sequences located on protein-coding messenger RNAs. Liang, K.H., Yeh, C.T. BMC. Genomics. (2013) [Pubmed]
  22. Artemis links ATM to double strand break rejoining. Jeggo, P.A., Löbrich, M. Cell Cycle (2005) [Pubmed]
  23. The DNA-dependent protein kinase interacts with DNA to form a protein-DNA complex that is disrupted by phosphorylation. Merkle, D., Douglas, P., Moorhead, G.B., Leonenko, Z., Yu, Y., Cramb, D., Bazett-Jones, D.P., Lees-Miller, S.P. Biochemistry (2002) [Pubmed]
  24. Apollo, an Artemis-related nuclease, interacts with TRF2 and protects human telomeres in S phase. van Overbeek, M., de Lange, T. Curr. Biol. (2006) [Pubmed]
  25. Interplay between Ku, Artemis, and the DNA-dependent protein kinase catalytic subunit at DNA ends. Drouet, J., Frit, P., Delteil, C., de Villartay, J.P., Salles, B., Calsou, P. J. Biol. Chem. (2006) [Pubmed]
  26. A new gene involved in DNA double-strand break repair and V(D)J recombination is located on human chromosome 10p. Moshous, D., Li, L., Chasseval, R., Philippe, N., Jabado, N., Cowan, M.J., Fischer, A., de Villartay, J.P. Hum. Mol. Genet. (2000) [Pubmed]
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