Genes encoding immunoglobulin heavy chains (Igh) are assembled by rearrangement of variable (V H), diversity (D H) and joining (J H) gene segments. Three critical constraints govern V H recombination. These include timing (V H recombination follows D H recombination), precision (V H gene segments recombine only to DJ H junctions) and allele specificity (V H recombination is restricted to DJ H-recombined alleles). Here we provide a model for these universal features of V H recombination. Analyses of DJ H-recombined alleles showed that DJ H junctions were selectively epigenetically marked, became nuclease sensitive and bound RAG recombinase proteins, which thereby permitted D H-associated recombination signal sequences to initiate the second step of Igh gene assembly. We propose that V H recombination is precise, because these changes did not extend to germline D H segments located 5′ of the DJ H junction.
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