Transcription factor Pax5 (BSAP) transactivates the RAG-mediated VH-to-DJH rearrangement of immunoglobulin genes

Immunoglobulin rearrangement from variable heavy chain (V-H) to diversity (D)-joining heavy chain (J(H)), which occurs exclusively in B lineage cells, is impaired in mice deficient for the B lineage-specific transcription factor Pax5. Conversely, ectopic Pax5 expression in thymocytes promotes the rearrangement of D-H-proximal V(H)7183 genes. In exploring the mechanism for Pax5 regulation of V-H-to-DJ(H) recombination, we have identified multiple Pax5 binding sites in the coding regions of human and mouse V-H gene segments. Pax5 bound to those sites in vitro and occupied V-H genes in early human and mouse B lineage cells. Moreover, Pax5 interacted with the recombination-activating gene 1 (RAG1)-RAG2 complex to enhance RAG-mediated V-H recombination signal sequence cleavage and recombination of a V-H gene substrate. These findings indicate a direct activating function for Pax5 in RAG-mediated immunoglobulin V-H-to-DJ(H) recombination.