title: The ataxia telangiectasia mutated kinase controls Igκ allelic exclusion by inhibiting secondary Vκ-to-Jκ rearrangements.
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 Igκ allelic exclusion, and that RAG DSBs induced during Igκ recombination in primary pre-B cells signal through ATM, but not DNA-PK, to suppress initiation of additional Igκ 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 Igκ allelic exclusion and suppress Igκ rearrangements. Upon activation in response to RAG Igκ cleavage, ATM signals down-regulation of Gadd45α with concomitant repression of the Gadd45α targets Rag1 and Rag2. Our data indicate that ATM kinases activated by RAG DSBs during Igκ recombination transduce transient H2AX/MDC1-independent signals that suppress initiation of further Igκ rearrangements to control Igκ allelic exclusion.
authors: Immunology Graduate Group, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors: Natalie C
authors: NC
authors: Steinel
authors: Baeck-Seung
authors: BS
authors: Lee
authors: Anthony T
authors: AT
authors: Tubbs
authors: Jeffrey J
authors: JJ
authors: Bednarski
authors: Emily
authors: E
authors: Schulte
authors: Katherine S
authors: KS
authors: Yang-Iott
authors: David G
authors: DG
authors: Schatz
authors: Barry P
authors: BP
authors: Sleckman
authors: Craig H
authors: CH
authors: Bassing
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000483:Alleles; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain; D006657:Histones / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D007145:Immunoglobulin kappa-Chains / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008954:Models, Biological; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D006657:Histones; D018398:Homeodomain Proteins; D007145:Immunoglobulin kappa-Chains; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; C508937:MDC1 protein, mouse; C499308:Rag2 protein, mouse; C064658:RAG-1 protein; C576325:Atm protein, mouse; C475961:gamma-H2AX protein, mouse
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