The Ataxia Telangiectasia mutated kinase controls Igκ allelic exclusion by inhibiting secondary Vκ-to-Jκ rearrangements

Allelic exclusion is enforced through the ability of antigen receptor chains expressed from one allele to signal feedback inhibition of V-to-(D)J recombination on the other allele. To achieve allelic exclusion by such means, only one allele can initiate V-to-(D) J recombination within the time required to signal feedback inhibition. DNA double-strand breaks (DSBs) induced by the RAG endonuclease during V(D) J recombination activate the Ataxia Telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK) kinases. We demonstrate that ATM enforces Ig kappa allelic exclusion, and that RAG DSBs induced during Ig kappa recombination in primary pre-B cells signal through ATM, but not DNA-PK, to suppress initiation of additional Ig kappa rearrangements. ATM promotes high-density histone H2AX phosphorylation to create binding sites for MDC1, which functions with H2AX to amplify a subset of ATM-dependent signals. However, neither H2AX nor MDC1 is required for ATM to enforce Ig kappa allelic exclusion and suppress Ig kappa rearrangements. Upon activation in response to RAG Ig kappa cleavage, ATM signals down-regulation of Gadd45. with concomitant repression of the Gadd45 alpha targets Rag1 and Rag2. Our data indicate that ATM kinases activated by RAG DSBs during Ig kappa recombination transduce transient H2AX/MDC1-independent signals that suppress initiation of further Ig kappa rearrangements to control Ig kappa allelic exclusion.