RAGged repair: what's new in V(D)J recombination.
Antigen-specific immunity is due to the generation of a multitude of both 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-specific recombination process. Hence, it became obvious that the initial steps of the reaction are carried out by the lymphocyte-specific proteins RAG1 and RAG2 (recombination-activating genes), with the help of members of the high mobility group protein family of DNA-binding proteins, HMG1 or HMG2. Structural resemblance between RAG1 and a prokaryotic recombinase, the Salmonella Hin Recombinase, together with mechanistic similarities between V(D)J recombination and bacterial transposition reactions, make it likely that these different processes have evolved from a common ancestral recombination system. The second step in V(D)J recombination is catalysed by the ubiquitous DNA double-strand break repair machinery. The link between V(D)J recombination and double-strand break repair was established through some mutational complementation groups, including the murine SCID mutation (severe combined immunodeficiency), which were shown to be defective in both V(D)J recombination and double-strand break repair. The multisubunit DNA-dependent protein kinase appears to be a key player in these processes. Thus, from an evolutionary point of view, antigen-specific immunity in mammals, e.g., humans and mice, appears to be the result of an evolutionary combination of two unrelated systems involved in DNA metabolism.
Hagmann
M
M
Institute of Molecular Biology II, University of Zürich, Switzerland.
D000818:Animals; D004260:DNA Repair; D016654:Genes, RAG-1 / Q000235:genetics*; D006801:Humans; D011995:Recombination, Genetic / Q000235:genetics*