Immunology

Recombination Combine

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Science  16 Apr 2004:
Vol. 304, Issue 5669, pp. 361-363
DOI: 10.1126/science.304.5669.361d

The resolution of DNA double-strand breaks (DSBs) is regulated in a context-dependent fashion that guards against aberrant genetic recombination. For example, although homologous recombination of DSBs is permitted during meiosis, it would be inappropriate in the somatic V(D)J recombination events that occur at the immunoglobulin loci. Instead, nonhomologous end joining (NHEJ) of DSBs takes place between V(D)J segments. This process involves formation of a postcleavage complex containing the DNA ends and the recombination activating gene (RAG) proteins.

Using an experimental system in which in vivo NHEJ and homologous recombination could be measured, Lee et al. found that expressing mutant RAG proteins (impaired in joining activity) produced a significant number of homologous recombination and alternative NHEJ events. These mutants formed unstable postcleavage complexes, suggesting that instability of the complex might render V(D)J intermediates available for inappropriate end-joining events; under normal circumstances, RAG proteins would guide DSB ends toward the NHEJ pathway. These results raise the possibility that RAG proteins could stimulate homologous recombination via single-strand nicking of DNA, perhaps leading to chromosomal translocations. — SJS

Cell 117, in press (2004).

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