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

• Consistent with a role for Artemis in repair of terminally blocked double strand breaks in vivo, human cells lacking Artemis exhibited hypersensitivity to x-rays, bleomycin, and neocarzinostatin, which all induce 3'-phosphoglycolate-terminated double strand breaks [9].

Biological context of DCLRE1C

• We demonstrate that Artemis is a downstream component of the ATM signaling pathway required uniquely for the DSB repair function but dispensable for ATM-dependent cell cycle checkpoint arrest [10].
• The DNA-dependent protein kinase catalytic subunit phosphorylation sites in human Artemis [11].
• Artemis is a DNA repair factor required for V(D)J recombination, repair of DNA damage induced by ionizing radiation (IR) or radiomimetic drugs, and the maintenance of genome integrity [12].
• The precise role of Artemis in the repair of IR-induced DNA damage remains to be elucidated [12].
• Artemis plays a crucial role in the hairpin-opening step of antigen receptor VDJ gene recombination in the presence of catalytic subunit of deoxyribonucleic acid (DNA)-dependent protein kinase (DNA-PKcs) [13].

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

• The kinase activity of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is necessary in activating Artemis as an endonuclease [11].
• The Artemis nuclease is defective in radiosensitive severe combined immunodeficiency patients and is required for the repair of a subset of ionising radiation induced DNA double-strand breaks (DSBs) in an ATM and DNA-PK dependent process [18].
• This defective recovery is due to promotion by mutant Artemis of an enhanced interaction between unphosphorylated cyclin B and Cdk1, which in turn promotes inhibitory phosphorylation of Cdk1 by the Wee1 kinase [20].
• DCLRE1C has sense Alu elements in its 3'UTR region, making it susceptible to the regulation of other protein-coding or non-coding RNAs with antisense Alu elements [21].

Other interactions of DCLRE1C

• Artemis links ATM to double strand break rejoining [22].
• We observe that Artemis phosphorylation occurs rapidly after irradiation like that of histone H2AX [1].
• Biochemical and genetic studies have shown that the DNA-dependent protein kinase (DNA-PK), XRCC4, DNA ligase IV, and Artemis are essential components of the nonhomologous end-joining pathway [23].
• Apollo, an Artemis-related nuclease, interacts with TRF2 and protects human telomeres in S phase [24].
• Using mass spectrometry of proteins associated with the shelterin component Rap1, we identified an SMN1/PSO2 nuclease family member that is closely related to Artemis [24].
• Altogether, our data allow us to propose a model in which a DNA-PKcs-mediated phosphorylation is necessary both to activate Artemis endonuclease activity and to maintain its association with the DNA end site [25].

Analytical, diagnostic and therapeutic context of DCLRE1C

• DNA PK-dependent phosphorylation of Artemis after treatment with DSB inducing agents increased the cellular retention of Artemis, maintained its interaction with DNA ends and activated its endonucleolytic activity [15].
• Protein sequence analysis strongly suggests that Artemis belongs to the metallo-beta-lactamase superfamily [8].
• Functional and biochemical dissection of the structure-specific nuclease ARTEMIS [17].
• Athabascan-speaking (SCIDA) Navajo and Apache Native Americans have a very high incidence of T(-)B(-)SCID [26].
• Immunogenotyping and immunophenotyping of bone marrow samples of 2 RS-SCID patients showed the absence of complete V(H)-J(H) gene rearrangements and consequently a complete B-cell differentiation arrest at the pre-B-cell receptor checkpoint-that is, at the transition from CyIgmu(-) pre-B-I cells to CyIgmu(+) pre-B-II cells [14].

References