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Blood, 26 March 2009, Vol. 113, No. 13, pp. 2965-2975. Prepublished online as a Blood First Edition Paper on January 6, 2009; DOI 10.1182/blood-2008-07-165167. This Article Full Text Full Text (PDF) Supplemental Methods, Tables, and Figures All Versions of this Article: blood-2008-07-165167v1 113/13/2965    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Giblin, W. Articles by Sekiguchi, J. Search for Related Content PubMed PubMed Citation Articles by Giblin, W. Articles by Sekiguchi, J. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Leaky severe combined immunodeficiency and aberrant DNA rearrangements due to a hypomorphic RAG1 mutation William Giblin1,*, Monalisa Chatterji2,*, Gerwin Westfield1,3, Tehmina Masud4, Brian Theisen3, Hwei-Ling Cheng5,6, Jeffrey DeVido6, Frederick W. Alt5,6, David O. Ferguson3, David G. Schatz2,5, and JoAnn Sekiguchi1,4 1 Department of Internal Medicine, University of Michigan, Ann Arbor; 2 Department of Immunobiology, Yale Medical School, New Haven, CT; Departments of 3 Pathology and 4 Human Genetics, University of Michigan, Ann Arbor; and 5 Howard Hughes Medical Institute and 6 The Children's Hospital, Immune Disease Institute, Department of Genetics, Harvard Medical School, Boston, MA The RAG1/2 endonuclease initiates programmed DNA rearrangements in progenitor lymphocytes by generating double-strand breaks at specific recombination signal sequences. This process, known as V(D)J recombination, assembles the vastly diverse antigen receptor genes from numerous V, D, and J coding segments. In vitro biochemical and cellular transfection studies suggest that RAG1/2 may also play postcleavage roles by forming complexes with the recombining ends to facilitate DNA end processing and ligation. In the current study, we examine the in vivo consequences of a mutant form of RAG1, RAG1-S723C, that is proficient for DNA cleavage, yet exhibits defects in postcleavage complex formation and end joining in vitro. We generated a knockin mouse model harboring the RAG1-S723C hypomorphic mutation and examined the immune system in this fully in vivo setting. RAG1-S723C homozygous mice exhibit impaired lymphocyte development and decreased V(D)J rearrangements. Distinct from RAG nullizygosity, the RAG1-S723C hypomorph results in aberrant DNA double-strand breaks within rearranging loci. RAG1-S723C also predisposes to thymic lymphomas associated with chromosomal translocations in a p53 mutant background, and heterozygosity for the mutant allele accelerates age-associated immune system dysfunction. Thus, our study provides in vivo evidence that implicates aberrant RAG1/2 activity in lymphoid tumor development and premature immunosenescence. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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