title: Leaky severe combined immunodeficiency and aberrant DNA rearrangements due to a hypomorphic RAG1 mutation.
abstract: 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.
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
authors.forename: William
authors.initials: W
authors.lastname: Giblin
authors.forename: Monalisa
authors.initials: M
authors.lastname: Chatterji
authors.forename: Gerwin
authors.initials: G
authors.lastname: Westfield
authors.forename: Tehmina
authors.initials: T
authors.lastname: Masud
authors.forename: Brian
authors.initials: B
authors.lastname: Theisen
authors.forename: Hwei-Ling
authors.initials: HL
authors.lastname: Cheng
authors.forename: Jeffrey
authors.initials: J
authors.lastname: DeVido
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Alt
authors.forename: David O
authors.initials: DO
authors.lastname: Ferguson
authors.forename: David G
authors.initials: DG
authors.lastname: Schatz
authors.forename: JoAnn
authors.initials: J
authors.lastname: Sekiguchi
mesh_terms: D000375:Aging / Q000235:genetics / Q000276:immunology; D019943:Amino Acid Substitution / Q000502:physiology; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D055879:Gene Knock-In Techniques; D015321:Gene Rearrangement / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006720:Homozygote; D008223:Lymphoma / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense / Q000502:physiology; D010641:Phenotype; D016511:Severe Combined Immunodeficiency / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D013953:Thymus Neoplasms / Q000235:genetics / Q000276:immunology; D050441:VDJ Exons
chemical_list: D018398:Homeodomain Proteins; C064658:RAG-1 protein