Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 5578K) PDF+supp data (7537K) PPT slides of all figures Supplemental Material Index Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Huang, Y. Articles by Sekiguchi, J. Search for Related Content PubMed PubMed Citation Articles by Huang, Y. Articles by Sekiguchi, J. Pubmed/NCBI databases Gene GEO Profiles HomoloGene Protein UniGene Substance via MeSH Social Bookmarking                            What's this?

Departments of Internal Medicine and Human Genetics, University of Michigan, Ann Arbor, MI 48109

CORRESPONDENCE JoAnn Sekiguchi: sekiguch{at}med.umich.edu

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.

Abbreviations used: cDNA, complementary DNA; DN, double negative; DNA-PKcs, DNA-dependent protein kinase catalytic subunit; DP, double positive; DSB, double-strand break; ES, embryonic stem; IgH, Ig heavy chain; IR, ionizing radiation; LM-PCR, ligation-mediated PCR; MBN, mung bean nuclease; MEF, mouse embryonic fibroblast; mRNA, messenger RNA; NHEJ, nonhomologous end joining; RAG, recombination activating gene; RSS, recombination signal sequence; RS-SCID, radiosensitive T^–B^– severe combined immunodeficiency.

© 2009 Huang et al.
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS