Transposition mediated by RAG1 and RAG2 and its implications for the evolution of the immune system.
Immunoglobulin and T-cell-receptor genes are assembled from component gene segments in developing lymphocytes by a site-specific recombination reaction, V(D)J recombination. The proteins encoded by the recombination-activating genes, RAG1 and RAG2, are essential in this reaction, mediating sequence-specific DNA recognition of well-defined recombination signals and DNA cleavage next to these signals. Here we show that RAG1 and RAG2 together form a transposase capable of excising a piece of DNA containing recombination signals from a donor site and inserting it into a target DNA molecule. The products formed contain a short duplication of target DNA immediately flanking the transposed fragment, a structure like that created by retroviral integration and all known transposition reactions. The results support the theory that RAG1 and RAG2 were once components of a transposable element, and that the split nature of immunoglobulin and T-cell-receptor genes derives from germline insertion of this element into an ancestral receptor gene soon after the evolutionary divergence of jawed and jawless vertebrates.
Agrawal
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A
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
Eastman
Q M
QM
Schatz
D G
DG
D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies / Q000235:genetics; D001402:B-Lymphocytes / Q000502:physiology; D001665:Binding Sites; D002384:Catalysis; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004251:DNA Transposable Elements; D004270:DNA, Circular / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004352:Drug Resistance, Microbial / Q000235:genetics; D019143:Evolution, Molecular; D015322:Gene Rearrangement, B-Lymphocyte; D015329:Gene Rearrangement, T-Lymphocyte; D006609:High Mobility Group Proteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D007107:Immune System / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D011995:Recombination, Genetic; D015183:Restriction Mapping; D019895:Transposases / Q000378:metabolism; D014714:Vertebrates / Q000235:genetics / Q000276:immunology
D000906:Antibodies; D004251:DNA Transposable Elements; D004270:DNA, Circular; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D018398:Homeodomain Proteins; C499308:Rag2 protein, mouse; D011948:Receptors, Antigen, T-Cell; C064655:V(D)J recombination activating protein 2; C064658:RAG-1 protein; D004247:DNA; D019895:Transposases