RAGGED REPAIR - WHATS NEW IN V(D)J RECOMBINATION

Antigen-specific immunity is due to the generation of a multitude of b oth immunoglobulins and T-cell receptors through a process designated V(D)J recombination, In vitro reconstitution of this system has taught us a great deal about the molecular mechanism underlying this site-sp ecific recombination process, Hence, it became obvious that the initia l steps of the reaction are carried out by the lymphocyte-specific pro teins RAG1 and RAG2 (recombination-activating genes), with the help of members of the high mobility group protein family of DNA-binding prot eins, HMG1 or HMG2, Structural resemblance between RAG1 and a prokaryo tic recombinase, the Salmonella Hin recombinase, together with mechani stic similarities between V(D)J recombination and bacterial transposit ion reactions, make it likely that these different processes have evol ved from a common ancestral recombination system. The second step in V (D)J recombination is catalysed by the ubiquitous DNA double-strand br eak repair machinery, The link between V(D)J recombination and double- strand break repair was established through some mutational complement ation groups, including the murine SCID mutation (severe combined immu nodeficiency), which were shown to be defective in both V(D)J recombin ation and double-strand break repair, The multisubunit DNA-dependent p rotein kinase appears to be a key player in these processes. Thus, fro m an evolutionary point of view, antigen-specific immunity in mammals, e.g., humans and mice, appears to be the result of an evolutionary co mbination of two unrelated systems involved in DNA metabolism.