VDJ Recombination

Artemis is the newest player in VDJ recombination and double strand break repair. First identified in radiation-sensitive and immune-deficient patients, it was recently shown to interact with DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and have nuclease activity, becoming the most popular candidate for the opening of hairpin coding ends. Reports presented in this issue (1) and in the December issue of Molecular Cell (2) address the role of Artemis in vivo by studying the effect of its deletion on the generation of intermediates and products of VDJ recombination in mouse ES cells, MEFs, and thy-mocytes. In all three systems analyzed, a defect in coding joint formation was observed, which was highly dependent on the cellular background and included inefficient and partially defective opening of hairpin coding ends. In addition, Artemis-deficient ES cells and Artemis-deficient MEFs show spontaneous chromosomal abnormalities, including telomere fusions, indicating that Artemis is also required for maintenance of genomic stability. This commentary will focus on the results regarding the role of Artemis in VDJ recombination. VDJ recombination, also known as antigen receptor gene rearrangement, is the process that assembles the variable domain of immunoglobulin and TCR genes. The hallmark of this reaction is the production of a large repertoire of antigen receptors with different specificities, a characteristic that is essential to the normal functioning of the immune system. VDJ recombination is directed to the immunoglobulin and TCR loci by highly conserved recombination signal sequences (RSSs) comprised of a heptamer and a nonamer motif with an intervening 12-or 23-bp spacer. Efficient re-combination in vivo occurs almost exclusively between RSSs with different spacers, which is referred to as the 12/ 23 rule (3). Several proteins that mediate VDJ recombina-tion in vivo have been identified (4). The lymphoid-specific components of the recombination machinery are RAG-1, RAG-2, and terminal deoxynucleotidyl transferase (TdT). RAG-1 and RAG-2 together constitute the recombinase. TdT, although not essential for catalysis, plays an important role increasing diversity by mediating the incorporation of nontemplate-dependent nucleotides. The nonlymphoid-restricted components identified so far are DNA-PKcs, Ku70, Ku80, XRCC4, ligase 4, and the most recently identified Artemis. All these proteins are involved in DNA double strand break repair as well as VDJ recombination. These nonlymphoid-specific components are likely to participate in the processing and joining steps of VDJ recombination, but their specific architectural or catalytic roles in the reaction remain largely unclear. Two other nonlymphoid-specific components, HMG1 and HMG2, have been …

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