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Impact of a hypomorphic Artemis disease allele on lymphocyte development, DNA end processing, and genome stability
- Source :
- The Journal of Experimental Medicine
- Publication Year :
- 2009
-
Abstract
- Artemis was initially discovered as the gene inactivated in human radiosensitive T−B− severe combined immunodeficiency, a syndrome characterized by the absence of B and T lymphocytes and cellular hypersensitivity to ionizing radiation. Hypomorphic Artemis alleles have also been identified in patients and are associated with combined immunodeficiencies of varying severity. We examine the molecular mechanisms underlying a syndrome of partial immunodeficiency caused by a hypomorphic Artemis allele using the mouse as a model system. This mutation, P70, leads to premature translation termination that deletes a large portion of a nonconserved C terminus. We find that homozygous Artemis-P70 mice exhibit reduced numbers of B and T lymphocytes, thereby recapitulating the patient phenotypes. The hypomorphic mutation results in impaired end processing during the lymphoid-specific DNA rearrangement known as V(D)J recombination, defective double-strand break repair, and increased chromosomal instability. Biochemical analyses reveal that the Artemis-P70 mutant protein interacts with the DNA-dependent protein kinase catalytic subunit and retains significant, albeit reduced, exo- and endonuclease activities but does not undergo phosphorylation. Together, our findings indicate that the Artemis C terminus has critical in vivo functions in ensuring efficient V(D)J rearrangements and maintaining genome integrity.
- Subjects :
- DNA damage
T-Lymphocytes
Immunology
Mice, Transgenic
Biology
medicine.disease_cause
Article
03 medical and health sciences
Mice
0302 clinical medicine
Mutant protein
Chromosome instability
medicine
Immunology and Allergy
Animals
Humans
Allele
Gene
030304 developmental biology
Gene Rearrangement
0303 health sciences
Mutation
Severe combined immunodeficiency
Genome
Genome, Human
Gene rearrangement
medicine.disease
Molecular biology
3. Good health
Disease Models, Animal
030220 oncology & carcinogenesis
RNA
Severe Combined Immunodeficiency
DNA Damage
Subjects
Details
- ISSN :
- 15409538
- Volume :
- 206
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- The Journal of experimental medicine
- Accession number :
- edsair.doi.dedup.....97b4eacdfc8f35aed35432f7f4d9c76d