{"doi":"10.4049/jimmunol.204.supp.223.12","title":"Elucidating the Role of NEMO and SpiC in DNA Double Strand Break Induced Inhibition of V(D)J Recombination","abstract":"<jats:title>Abstract</jats:title>\n               <jats:p>V(D)J recombination is regulated such that most lymphocytes assemble and express an antigen receptor from only one allele (allelic exclusion). In pre-B cells, RAG-induced DNA double strand breaks (DSBs) at Igκ loci signal via ATM to rapidly repress Rag1/2 transcription, inhibit accessibility of Igk loci, and limit V recombination. We hypothesize that RAG DSB-induced repression of Rag1/2 is critical to transiently limit V recombination, ensure allelic exclusion, and inhibit oncogenic Ig translocations. Fittingly, Atm − / − mice have higher frequencies of developing B cells with RAG DSBs at both Igh and Igk loci and of mature B cells with bi-allelic expression of these genes. Yet, given the multifunctional roles of ATM in the DSB response, Atm − / − phenotypes cannot be directly attributed to Rag1/2 repression. To test our hypothesis, we study mouse models lacking downstream effectors of ATM: i) SpiC, which suppresses Igk accessibility in response to RAG DSBs, and ii) NFκB essential modulator (NEMO), which represses Rag1/2 in response to genotoxic DSBs. I show here that the frequency of surface bi-allelic Igκ expression is normal on SpiC − / − B cells and increased on Nemo − / − B cells. I also show that Nemo − / − pre-B cells exhibit impaired Rag1/2 repression in response to RAG DSBs and concomitant increased RAG cleavage at Igk. Our data support that RAG DSB-induced repression of Rag1/2 transiently inhibits additional Igk rearrangements to enforce Igκ allelic exclusion independent of ATM-mediated DSB repair. I am using Nemo−/− mouse models to determine if DSB-induced Rag1/2 repression requires Nemo in pro-B cells, and if this mechanism is critical to suppress oncogenic Ig translocations independent of defects in DSB repair/checkpoint activation.</jats:p>","journal":"The Journal of Immunology","year":2020,"id":654439,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1339881,"name":"Craig Bassing","orcid":null,"position":1,"is_corresponding":false},{"id":1707977,"name":"Rebecca Glynn","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Elucidating the Role of NEMO and SpiC in DNA Double Strand Break Induced Inhibition of V(D)J Recombination","abstract":"<jats:title>Abstract</jats:title>\n               <jats:p>V(D)J recombination is regulated such that most lymphocytes assemble and express an antigen receptor from only one allele (allelic exclusion). In pre-B cells, RAG-induced DNA double strand breaks (DSBs) at Igκ loci signal via ATM to rapidly repress Rag1/2 transcription, inhibit accessibility of Igk loci, and limit V recombination. We hypothesize that RAG DSB-induced repression of Rag1/2 is critical to transiently limit V recombination, ensure allelic exclusion, and inhibit oncogenic Ig translocations. Fittingly, Atm − / − mice have higher frequencies of developing B cells with RAG DSBs at both Igh and Igk loci and of mature B cells with bi-allelic expression of these genes. Yet, given the multifunctional roles of ATM in the DSB response, Atm − / − phenotypes cannot be directly attributed to Rag1/2 repression. To test our hypothesis, we study mouse models lacking downstream effectors of ATM: i) SpiC, which suppresses Igk accessibility in response to RAG DSBs, and ii) NFκB essential modulator (NEMO), which represses Rag1/2 in response to genotoxic DSBs. I show here that the frequency of surface bi-allelic Igκ expression is normal on SpiC − / − B cells and increased on Nemo − / − B cells. I also show that Nemo − / − pre-B cells exhibit impaired Rag1/2 repression in response to RAG DSBs and concomitant increased RAG cleavage at Igk. Our data support that RAG DSB-induced repression of Rag1/2 transiently inhibits additional Igk rearrangements to enforce Igκ allelic exclusion independent of ATM-mediated DSB repair. I am using Nemo−/− mouse models to determine if DSB-induced Rag1/2 repression requires Nemo in pro-B cells, and if this mechanism is critical to suppress oncogenic Ig translocations independent of defects in DSB repair/checkpoint activation.</jats:p>","is_dataset_classified":null,"base_score":0.0,"endowment":0.0,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"19965766","pmcid":null,"openalex_id":"https://openalex.org/W4313373485","authors":[],"funders":[],"total_grants":0,"fwci":null,"citation_percentile":null,"influential_citations":0,"citation_trend":[],"oa_status":"closed","license":"https://academic.oup.com/pages/standard-publication-reuse-rights","oa_locations":[{"url":"https://academic.oup.com/jimmunol/article/204/1_Supplement/223.12/7950258","host_type":"publisher"},{"url":"https://doi.org/10.4049/jimmunol.204.supp.223.12","host_type":"journal"}],"fields_of_study":["T-cell and B-cell Immunology","Immune Cell Function and Interaction","DNA Repair Mechanisms"],"mesh_terms":[],"keywords":["Recombination-activating gene","Allelic exclusion","V(D)J recombination","Molecular biology","Biology","Recombination signal sequences","RAG2","Recombination","DNA","Psychological repression","Gene","Genetics","Gene expression","T-cell receptor","T cell"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Reduced inequalities"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-11T06:39:33.338408Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}