Journal article Open Access

Recombination-activating gene proteins: more regulation, please

Sadofsky, Moshe J.

During V(D)J recombination, developing B and T cells assemble gene segments in order to create the variable regions of immunoglobulin and T cell receptors required by our adaptive immune response. The chemistry of this recombination pathway requires a specific nuclease, and a more general repair pathway for double strand breaks. The nuclease activity is provided by a complex of the RAG1 and RAG2 proteins. In fact, RAG1 and RAG2 probably coordinate many steps involving the coding and signal DNA sequences. Studies using deletion and truncation mutants of the RAG proteins demonstrate that each of these contain a functional core region, representing about two-thirds of each polypeptide, While the core regions are sufficient to catalyze recombination in test systems, the full-length proteins seem to show more complicated behaviors in vivo. A plausible explanation is that regions outside the core help in the proper regulation of recombination. The non-core region of RAG1 has just been found to contain a ubiquitin ligase. Regulatory functions may contribute to autoregulation of the proteins involved, fidelity of the reaction, protection of the cell from translocations, coordination of recombination with the cell-cycle and possibly modification of the chromatin structure of target DNA.

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