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.The immune system's vast repertoire of B-and T-cell receptors results from a site-specific gene rearrangement process known as V(D)J recombination. Assorted variable (V), diversity (D), and joining (J) coding gene segments are recombined in developing lymphocyte precursors to form the variable region genes that encode antigen-binding sites of immunoglobulin and T-cell receptor molecules (40). The DNA is first cleaved at specific recombination signal sequences (RSS) located adjacent to the coding segments. RSS consist of conserved heptamer and nonamer sequences, separated by either 12 or 23 nucleotides of spacer DNA (referred to as 12 RSS and 23 RSS). The RAG1 and RAG2 recombinase proteins, assisted by either of the nonspecific DNA-bending proteins HMG1 and HMG2 (41), generate a nick between the RSS and the adjacent coding segment by hydrolysis. The newly formed 3Ј OH group then attacks the phosphodiester bond connecting the coding segment to the RSS on the opposite strand.