title: Collaboration of RAG2 with RAG1-like proteins during the evolution of V(D)J recombination.
abstract: The recombination-activating gene 1 (RAG1) and RAG2 proteins initiate V(D)J recombination, the process that assembles the B- and T-lymphocyte antigen receptor genes of jawed vertebrates. RAG1 and RAG2 are thought to have arisen from a transposable element, but the origins of this element are not understood. We show that two ancestral RAG1 proteins, Transib transposase and purple sea urchin RAG1-like, have a latent ability to initiate V(D)J recombination when coexpressed with RAG2 and that in vitro transposition by Transib transposase is stimulated by RAG2. Conversely, we report low levels of V(D)J recombination by RAG1 in the absence of RAG2. Recombination by RAG1 alone differs from canonical V(D)J recombination in having lost the requirement for asymmetric DNA substrates, implicating RAG2 in the origins of the "12/23 rule," a fundamental regulatory feature of the reaction. We propose that evolution of RAG1/RAG2 began with a Transib transposon whose intrinsic recombination activity was enhanced by capture of an ancestral RAG2, allowing for the development of adaptive immunity.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, 06520, USA;
authors.forename: Lina Marcela
authors.initials: LM
authors.lastname: Carmona
authors.affiliation: Department of Biomedical Sciences, Chang Gung University, Tao-Yuan City 33302, Taiwan; Chang Gung Immunology Consortium, Chang Gung Memorial Hospital, Chang Gung University, Tao-Yuan City 33302, Taiwan;
authors.forename: Sebastian D
authors.initials: SD
authors.lastname: Fugmann
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, 06520, USA; Howard Hughes Medical Institute, New Haven, Connecticut 06511, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Schatz
mesh_terms: D016475:3T3 Cells; D056704:Adaptive Immunity / Q000235:genetics; D000818:Animals; D004251:DNA Transposable Elements / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019143:Evolution, Molecular; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D047270:Strongylocentrotus purpuratus / Q000235:genetics; D019895:Transposases / Q000378:metabolism; D060152:V(D)J Recombination / Q000235:genetics*
chemical_list: D004251:DNA Transposable Elements; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C064655:V(D)J recombination activating protein 2; C064658:RAG-1 protein; D019895:Transposases
keywords: RAG; Transib; V(D)J recombination; evolution; transposition