6wnl

Structural highlights

Disease

DCR1C_HUMAN Severe combined immunodeficiency, alymphocytotic type;Omenn syndrome. Defects in DCLRE1C are a cause of severe combined immunodeficiency autosomal recessive T-cell-negative/B-cell-negative/NK-cell-positive with sensitivity to ionizing radiation (RSSCID) [MIM:602450. SCID refers to a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients with SCID present in infancy with recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development. Individuals affected by RS-SCID show defects in the DNA repair machinery necessary for coding joint formation and the completion of V(D)J recombination. A subset of cells from such patients show increased radiosensitivity.^{[1] [2] [3] [4] [5]} Defects in DCLRE1C are the cause of severe combined immunodeficiency Athabaskan type (SCIDA) [MIM:602450. SCIDA is a variety of RS-SCID caused by a founder mutation in Athabascan-speaking native Americans, being inherited as an autosomal recessive trait with an estimated gene frequency of 2.1% in the Navajo population. Affected individuals exhibit clinical symptoms and defects in DNA repair comparable to those seen in RS-SCID.^[6] Defects in DCLRE1C are a cause of Omenn syndrome (OS) [MIM:603554. OS is characterized by severe combined immunodeficiency associated with erythrodermia, hepatosplenomegaly, lymphadenopathy and alopecia. Affected individuals have elevated T-lymphocyte counts with a restricted T-cell receptor (TCR) repertoire. They also generally lack B-lymphocytes, but have normal natural killer (NK) cell function (T+ B- NK+).

Function

DCR1C_HUMAN Required for V(D)J recombination, the process by which exons encoding the antigen-binding domains of immunoglobulins and T-cell receptor proteins are assembled from individual V, (D), and J gene segments. V(D)J recombination is initiated by the lymphoid specific RAG endonuclease complex, which generates site specific DNA double strand breaks (DSBs). These DSBs present two types of DNA end structures: hairpin sealed coding ends and phosphorylated blunt signal ends. These ends are independently repaired by the non homologous end joining (NHEJ) pathway to form coding and signal joints respectively. This protein exhibits single-strand specific 5'-3' exonuclease activity in isolation and acquires endonucleolytic activity on 5' and 3' hairpins and overhangs when in a complex with PRKDC. The latter activity is required specifically for the resolution of closed hairpins prior to the formation of the coding joint. May also be required for the repair of complex DSBs induced by ionizing radiation, which require substantial end-processing prior to religation by NHEJ.^{[7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17]}

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. 2001 Apr 20;105(2):177-86. PMID:11336668
2. ↑ 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. 2003 Feb 15;101(4):1446-52. Epub 2002 Oct 24. PMID:12406895 doi:10.1182/blood-2002-01-0187
3. ↑ 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. 2003 Aug;108(2):159-66. PMID:12921762
4. ↑ 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. 2003 Apr;112(4):348-52. Epub 2003 Feb 19. PMID:12592555 doi:10.1007/s00439-002-0897-x
5. ↑ Moshous D, Pannetier C, Chasseval Rd Rd, Deist Fl Fl, Cavazzana-Calvo M, Romana S, Macintyre E, Canioni D, Brousse N, Fischer A, Casanova JL, Villartay JP. Partial T and B lymphocyte immunodeficiency and predisposition to lymphoma in patients with hypomorphic mutations in Artemis. J Clin Invest. 2003 Feb;111(3):381-7. PMID:12569164 doi:10.1172/JCI16774
6. ↑ 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. 2002 Jun 15;168(12):6323-9. PMID:12055248
7. ↑ 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. 2001 Apr 20;105(2):177-86. PMID:11336668
8. ↑ 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. 2002 Jun 15;168(12):6323-9. PMID:12055248
9. ↑ 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. 2002 Mar 22;108(6):781-94. PMID:11955432
10. ↑ Pannicke U, Ma Y, Hopfner KP, Niewolik D, Lieber MR, Schwarz K. Functional and biochemical dissection of the structure-specific nuclease ARTEMIS. EMBO J. 2004 May 5;23(9):1987-97. Epub 2004 Apr 8. PMID:15071507 doi:10.1038/sj.emboj.7600206
11. ↑ Poinsignon C, de Chasseval R, Soubeyrand S, Moshous D, Fischer A, Hache RJ, de Villartay JP. Phosphorylation of Artemis following irradiation-induced DNA damage. Eur J Immunol. 2004 Nov;34(11):3146-55. PMID:15468306 doi:10.1002/eji.200425455
12. ↑ 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. 2004 Feb 2;199(3):315-21. Epub 2004 Jan 26. PMID:14744996 doi:10.1084/jem.20031142
13. ↑ Ma Y, Lu H, Tippin B, Goodman MF, Shimazaki N, Koiwai O, Hsieh CL, Schwarz K, Lieber MR. A biochemically defined system for mammalian nonhomologous DNA end joining. Mol Cell. 2004 Dec 3;16(5):701-13. PMID:15574326 doi:10.1016/j.molcel.2004.11.017
14. ↑ Riballo E, Kuhne 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, Lobrich M. A pathway of double-strand break rejoining dependent upon ATM, Artemis, and proteins locating to gamma-H2AX foci. Mol Cell. 2004 Dec 3;16(5):715-24. PMID:15574327 doi:S1097276504006549
15. ↑ 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. 2004 Oct;24(20):9207-20. PMID:15456891 doi:10.1128/MCB.24.20.9207-9220.2004
16. ↑ Wang J, Pluth JM, Cooper PK, Cowan MJ, Chen DJ, Yannone SM. Artemis deficiency confers a DNA double-strand break repair defect and Artemis phosphorylation status is altered by DNA damage and cell cycle progression. DNA Repair (Amst). 2005 May 2;4(5):556-70. PMID:15811628 doi:S1568-7864(05)00052-2
17. ↑ Ma Y, Schwarz K, Lieber MR. The Artemis:DNA-PKcs endonuclease cleaves DNA loops, flaps, and gaps. DNA Repair (Amst). 2005 Jul 12;4(7):845-51. PMID:15936993 doi:S1568-7864(05)00097-2