Nonhomologous End-joining Proteins Are Required for V(D)J Recombination, Normal Growth, and Neurogenesis

During B- and T-lymphocyte development, immunoglobulin (Ig) and T-cell receptor (TCR) genes areassembled from multiple V, D, and J coding gene segments by V(D)J recombination (for review, see Willerford et al. 1996). V(D)J recombination employs a specificDNA double-strand break (DSB) initiated by the recombination activating gene proteins 1 and 2 (RAG1 andRAG2), which are the required, tissue-specific components of the V(D)J recombinase. Thus, targeted inactivation of either RAG1 or RAG2 in mice leads to a lack of Bor T lymphocytes (severe combined immune deficiency)due to inability to initiate V(D)J recombination; however,RAG-deficient mice have no other reported defects(Mombaerts et al. 1992; Shinkai et al. 1992). RAGscleave at recombination signal sequences (RSSs) locatedadjacent to each V, D, or J coding exon, resulting in formation of hairpin coding ends and blunt, 5′ phosphorylated RS ends (for review, see Gellert 1997). RS ends areprecisely joined; however, prior to ligation, hairpin coding ends must be opened and nucleotides can be added ordeleted to generate junctional diversity. The nontemplated nucleotide addition process is carried out by terminal deoxynucleotidyl transferase (TdT), the only otheridentified lymphoid-specific V(D)J component (Komoriet al. 1993; Gilfillan et al. 1994). Joining of both codingand RS ends requires ubiquitously expressed proteins,which also are involved in general DNA double-strandbreak repair (DSBR) via a nonhomologous end-joining(NHEJ) reaction (for review, see Jeggo 1998)...