The Ataxia Telangiectasia mutated kinase controls Ig? allelic exclusion by inhibiting secondary V?-to-J? rearrangements.

The Ataxia Telangiectasia mutated kinase controls Ig? allelic exclusion by inhibiting secondary V?-to-J? rearrangements.

J Exp Med. 2013 Feb 4;

Authors: Steinel NC, Lee BS, Tubbs AT, Bednarski JJ, Schulte E, Yang-Iott KS, Schatz DG, Sleckman BP, Bassing CH

Abstract
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? allelic exclusion, and that RAG DSBs induced during Ig? recombination in primary pre-B cells signal through ATM, but not DNA-PK, to suppress initiation of additional Ig? 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? allelic exclusion and suppress Ig? rearrangements. Upon activation in response to RAG Ig? cleavage, ATM signals down-regulation of Gadd45? with concomitant repression of the Gadd45? targets Rag1 and Rag2. Our data indicate that ATM kinases activated by RAG DSBs during Ig? recombination transduce transient H2AX/MDC1-independent signals that suppress initiation of further Ig? rearrangements to control Ig? allelic exclusion.

PMID: 23382544 [PubMed - as supplied by publisher]

ecdysone chir-258 dovitinib