{"doi":"10.1101/2021.06.28.450246","title":"Rad52 mediates class-switch DNA recombination to IgD","abstract":"While the biology of IgD begins to be better understood, the mechanism of expression of this phylogenetically old and highly conserved Ig remains unknown. In B cells, IgD is expressed together with IgM as transmembrane receptor for antigen through alternative splicing of long primary V H DJ H -Cμ-s-m-Cδ-s-m RNAs, which also underpin secreted (s)IgD. IgD is also expressed through class switch DNA recombination (CSR), as initiated by AID-mediated double-strand DNA breaks (DSBs) in Sμ and σδ, and resolution of such DSBs by a still unknown mechanism. This synapses Sμ with σδ region DSB resected ends leading to insertion of extensive S-S junction microhomologies, unlike Ku70/Ku86-dependent NHEJ which resolves DSB blunt ends in CSR to IgG, IgA and IgE with little or no microhomologies. Our previous demonstration of a novel role of Rad52 in a Ku70/Ku86-independent “short-range” microhomology-mediated synapsis of intra-Sμ region DSBs led us to hypothesize that this homologous recombination DNA annealing factor is also involved in short-range microhomology-mediated alternative endjoining (A-EJ) recombination of Sμ with σδ. We found that induction of IgD CSR by selected stimuli downregulated Zfp318 (the suppressor of Cμ-s-m transcription termination), promoted Rad52 phosphorylation and Rad52 recruitment to Sμ and σδ, leading to Sμ-σδ recombination with extensive microhomologies, V H DJ H -Cδs transcription and sustained IgD secretion. Rad52 ablation in mouse Rad52 −/− B cells aborted IgD CSR in vitro and in vivo and dampened the specific IgD antibody response to OVA. Further, Rad52 knockdown in human B cells virtually abrogated IgD CSR. Finally, Rad52 phosphorylation was associated with high levels of IgD CSR and anti-nuclear IgD autoantibodies in lupus-prone mice and lupus patients. Thus, Rad52 effects CSR to IgD through microhomology-mediated A-EJ and in concert with Zfp318 modulation. This is a previously unrecognized, critical and dedicated role of Rad52 in mammalian DNA repair that provides a mechanistic underpinning to CSR A-EJ.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":225423,"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":0.9535,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":827851,"name":"Hang Zhou","orcid":"0000-0001-6815-9999","position":1,"is_corresponding":false},{"id":761797,"name":"Ginell R. Post","orcid":"0000-0003-2877-4860","position":2,"is_corresponding":false},{"id":231705,"name":"Hong Zan","orcid":"0000-0002-2873-7034","position":3,"is_corresponding":false},{"id":231706,"name":"Paolo Casali","orcid":"0000-0002-8982-5177","position":4,"is_corresponding":false},{"id":827850,"name":"Yijiang Xu","orcid":"0000-0001-6597-1105","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:54:26.581453Z","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":[]}