Targeted transposition by the V(D)J recombinase.
Cleavage by the V(D)J recombinase at a pair of recombination signal sequences creates two coding ends and two signal ends. The RAG proteins can integrate these signal ends, without sequence specificity, into an unrelated target DNA molecule. Here we demonstrate that such transposition events are greatly stimulated by--and specifically targeted to--hairpins and other distorted DNA structures. The mechanism of target selection by the RAG proteins thus appears to involve recognition of distorted DNA. These data also suggest a novel mechanism for the formation of alternative recombination products termed hybrid joints, in which a signal end is joined to a hairpin coding end. We suggest that hybrid joints may arise by transposition in vivo and propose a new model to account for some recurrent chromosome translocations found in human lymphomas. According to this model, transposition can join antigen receptor loci to partner sites that lack recombination signal sequence elements but bear particular structural features. The RAG proteins are capable of mediating all necessary breakage and joining events on both partner chromosomes; thus, the V(D)J recombinase may be far more culpable for oncogenic translocations than has been suspected.
Lee
Gregory S
GS
Department of Immunology, Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, USA.
Neiditch
Matthew B
MB
Sinden
Richard R
RR
Roth
David B
DB
D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D006224:Cricetinae; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004254:DNA Nucleotidyltransferases / Q000378:metabolism*; D026942:DNA Topoisomerases / Q000378:metabolism; D004251:DNA Transposable Elements / Q000235:genetics*; D004274:DNA, Recombinant / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D015321:Gene Rearrangement / Q000235:genetics; D018390:Gene Targeting; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D009690:Nucleic Acid Conformation; D016133:Polymerase Chain Reaction; D011995:Recombination, Genetic / Q000235:genetics*; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics; D013379:Substrate Specificity; D014178:Translocation, Genetic / Q000235:genetics; D045567:VDJ Recombinases
D004251:DNA Transposable Elements; D004274:DNA, Recombinant; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D009687:Nuclear Proteins; C499311:RAG2 protein, human; C064655:V(D)J recombination activating protein 2; C064658:RAG-1 protein; D004247:DNA; D004254:DNA Nucleotidyltransferases; D045567:VDJ Recombinases; D026942:DNA Topoisomerases