{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:51:17Z","timestamp":1790805077341,"version":"4.1.0"},"reference-count":30,"publisher":"Rockefeller University Press","issue":"2","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2013,2,11]]},"abstract":"<jats:p>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\u03ba allelic exclusion, and that RAG DSBs induced during Ig\u03ba recombination in primary pre\u2013B cells signal through ATM, but not DNA-PK, to suppress initiation of additional Ig\u03ba 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\u03ba allelic exclusion and suppress Ig\u03ba rearrangements. Upon activation in response to RAG Ig\u03ba cleavage, ATM signals down-regulation of Gadd45\u03b1 with concomitant repression of the Gadd45\u03b1 targets Rag1 and Rag2. Our data indicate that ATM kinases activated by RAG DSBs during Ig\u03ba recombination transduce transient H2AX\/MDC1-independent signals that suppress initiation of further Ig\u03ba rearrangements to control Ig\u03ba allelic exclusion.<\/jats:p>","DOI":"10.1084\/jem.20121605","type":"journal-article","created":{"date-parts":[[2013,2,4]],"date-time":"2013-02-04T23:01:37Z","timestamp":1360018897000},"page":"233-239","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":45,"title":["The Ataxia Telangiectasia mutated kinase controls Ig\u03ba allelic exclusion by inhibiting secondary\n                    <i>V\u03ba<\/i>\n                    -to-\n                    <i>J\u03ba<\/i>\n                    rearrangements"],"prefix":"10.1084","volume":"210","author":[{"given":"Natalie C.","family":"Steinel","sequence":"first","affiliation":[{"name":"Immunology Graduate Group 1 , and 2"},{"name":"Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104 1 , and 2"},{"name":"Immunology Graduate Group 1 , and 2"},{"name":"Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104 1 , and 2"},{"name":"Division of Cancer Pathobiology, Department of Pathology and Laboratory Medicine, Center for Childhood Cancer Research, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baeck-Seung","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology 4 and 5"},{"name":"Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110 4 and 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony T.","family":"Tubbs","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology 4 and 5"},{"name":"Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110 4 and 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey J.","family":"Bednarski","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology 4 and 5"},{"name":"Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110 4 and 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Schulte","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology 4 and 5"},{"name":"Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110 4 and 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine S.","family":"Yang-Iott","sequence":"additional","affiliation":[{"name":"Division of Cancer Pathobiology, Department of Pathology and Laboratory Medicine, Center for Childhood Cancer Research, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David G.","family":"Schatz","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520 6"},{"name":"Howard Hughes Medical Institute, New Haven, CT 06520 7"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barry P.","family":"Sleckman","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology 4 and 5"},{"name":"Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110 4 and 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig H.","family":"Bassing","sequence":"additional","affiliation":[{"name":"Immunology Graduate Group 1 , and 2"},{"name":"Abramson Family Cancer Research Institute, Department of Pathology 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