Disease relevance of Dclre1c

• Targeted disruption of the Artemis murine counterpart results in SCID and defective V(D)J recombination that is partially corrected with bone marrow transplantation [1].
• Because Art deficient mice represent a model for radiation-sensitive severe combined immunodeficiency, our findings suggest that these patients may be at risk for both lymphoid and non-lymphoid cancers [2].
• We demonstrate a key role for ARTEMIS in sarcoma suppression in a sensitized mouse tumor model [3].

High impact information on Dclre1c

• Artemis gene mutations are responsible for the development of a severe combined immunodeficiency [radiation-sensitive (RS) SCID] characterized by a severe B and T cell deficiency and a normal natural killer cell population [4].
• To establish the feasibility of a gene therapy approach to the treatment of RS-SCID, we generated a series of lentiviral vectors expressing human Artemis from different promoters and used them to transduce highly purified hematopoietic stem cells (HSCs) from Artemis knockout mice [4].
• HSCs transduced by the different viruses were transplanted into either lethally irradiated Rag-1-deficient animals or Artemis knockout mice treated with a nonmyeloablative dose of Busulfan [4].
• We found that Artemis-deficient HL B cells undergo robust CSR, indicating that DNA-PKcs functions in CSR via an Artemis-independent mechanism [5].
• In this report, we show that Artemis/p53-deficient mice also succumb reproducibly to progenitor B cell tumors, demonstrating that Artemis is a tumor suppressor in mice [6].

Biological context of Dclre1c

• Artemis-deficient mice show a similar T-B- NK+ immunodeficiency phenotype, and carry a profound impairment in coding joint rearrangement, while retaining intact signal ends and close to normal signal joint formation. mArt-/- embryonic fibroblasts show increased sensitivity to ionizing radiation [1].
• Our results suggest that the V(D)J and DNA repair defects seen in this mArt-/- mouse model are comparable to those in humans with Artemis deficiency, and that the recovery of immunity following HSC transplantation favors T rather than B cell reconstitution, consistent with what is seen in children with this form of SCID [1].
• Because mice with combined disruptions of ATM and other NHEJ components (ligase IV, Artemis) are viable, our data suggest a novel NHEJ-independent function for Prkdc/Ku that is required to complete early embryogenesis in the absence of ATM [7].
• The RUNX3 gene, whose coded protein binds to the enhancers of TR genes, was also modulated and the DNA cross-linking LR1 gene, which plays a role in the opening of hairpin DNA structures and whose expression pattern is similar to Artemis, may play a role in the control of V(D)J recombination [8].

Anatomical context of Dclre1c

• To obviate the requirement for V(D)J recombination, we generated DNA-PKcs- and Artemis-deficient B cells that harbored preassembled Ig heavy chain and kappa-light chain "knock-in" (HL) alleles [5].

Other interactions of Dclre1c

• Therefore, we conclude that DNA-PKcs has Artemis-independent functions in CSR and normal development [5].
• Clustering analysis showed similar expression profiling of genes implicated in the V(D)J recombination and DNA double strand break (DSB) repair processes such as XRCC4, RAG-2, Artemis and DNA-PK-cs, thus suggesting overlap between the two processes [8].

References