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AgR allelic exclusion is achieved by sequential initiation of V(D)J recombination between alleles and resultant protein from one allele signaling to prevent recombination of the other. The ATM kinase, a regulator of the DNA double-strand break (DSB) response, helps enforce allelic exclusion through undetermined mechanisms. ATM promotes repair of RAG1\/RAG2 (RAG) endonuclease-induced DSBs and transduces signals from RAG DSBs during Igk gene rearrangement on one allele to transiently inhibit RAG1 protein expression, Igk accessibility, and RAG cleavage of the other allele. Yet, the relative contributions of ATM functions in DSB repair versus signaling to enforce AgR allelic exclusion remain undetermined. In this study, we demonstrate that inactivation in mouse pre\u2013B cells of the NF-\u03baB essential modulator (Nemo) protein, an effector of ATM signaling, diminishes RAG DSB\u2013triggered repression of Rag1\/Rag2 transcription and Igk accessibility but does not result in aberrant repair of RAG DSBs like ATM inactivation. We show that Nemo deficiency increases simultaneous biallelic Igk cleavage in pre\u2013B cells and raises the frequency of B cells expressing Ig\u03ba proteins from both alleles. In contrast, the incidence of biallelic Ig\u03ba expression is not elevated by inactivation of the SpiC transcriptional repressor, which is induced by RAG DSBs in an ATM-dependent manner and suppresses Igk accessibility. Thus, we conclude that Nemo-dependent, ATM-mediated DNA damage signals enforce Ig\u03ba allelic exclusion by orchestrating transient repression of RAG expression and feedback inhibition of additional Igk rearrangements in response to RAG cleavage on one Igk allele.<\/jats:p>","DOI":"10.4049\/jimmunol.2100696","type":"journal-article","created":{"date-parts":[[2021,12,29]],"date-time":"2021-12-29T20:20:34Z","timestamp":1640809234000},"page":"371-383","source":"Crossref","is-referenced-by-count":8,"title":["Nemo-Dependent, ATM-Mediated Signals from RAG DNA Breaks at <i>Igk<\/i> Feedback Inhibit <i>V<\/i>\n                  <i>\u03ba<\/i> Recombination to Enforce Ig\u03ba Allelic Exclusion"],"prefix":"10.1093","volume":"208","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3916-6900","authenticated-orcid":false,"given":"Rebecca A","family":"Glynn","sequence":"first","affiliation":[{"name":"Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA; and , Philadelphia, PA"},{"name":"Department of Pathology and Laboratory Medicine, Children\u2019s Hospital of Pennsylvania , Philadelphia, PA; and , Philadelphia, PA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1703-0786","authenticated-orcid":false,"given":"Craig H","family":"Bassing","sequence":"additional","affiliation":[{"name":"Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA; and , Philadelphia, PA"},{"name":"Department of Pathology and Laboratory Medicine, Children\u2019s Hospital of Pennsylvania , Philadelphia, PA; and , Philadelphia, PA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2022,1,15]]},"reference":[{"key":"2025021008502580800_r1","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1146\/annurev-genet-110410-132552","article-title":"V(D)J recombination: mechanisms of initiation","volume":"45","author":"Schatz","year":"2011","journal-title":"Annu. 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