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.
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
A
A
Agrawal
Q M
QM
Eastman
D G
DG
Schatz
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