{"doi":"10.1073/pnas.2103630118","title":"Ku70 suppresses alternative end joining in G1-arrested progenitor B cells","abstract":"Classical nonhomologous end joining (C-NHEJ) repairs DNA double-strand breaks (DSBs) throughout interphase but predominates in G1 phase when homologous recombination is unavailable. Complexes containing the Ku70/80 (\"Ku\") and XRCC4/ligase IV (Lig4) core C-NHEJ factors are required, respectively, for sensing and joining DSBs. While XRCC4/Lig4 are absolutely required for joining RAG1/2 endonuclease (\"RAG\")-initiated DSBs during V(D)J recombination in G1-phase progenitor lymphocytes, cycling cells deficient for XRCC4/Lig4 also can join chromosomal DSBs by alternative end-joining (A-EJ) pathways. Restriction of V(D)J recombination by XRCC4/Lig4-mediated joining has been attributed to RAG shepherding V(D)J DSBs exclusively into the C-NHEJ pathway. Here, we report that A-EJ of DSB ends generated by RAG1/2, Cas9:gRNA, and Zinc finger endonucleases in Lig4-deficient G1-arrested progenitor B cell lines is suppressed by Ku. Thus, while diverse DSBs remain largely as free broken ends in Lig4-deficient G1-arrested progenitor B cells, deletion of Ku70 increases DSB rejoining and translocation levels to those observed in Ku70-deficient counterparts. Correspondingly, while RAG-initiated V(D)J DSB joining is abrogated in Lig4-deficient G1-arrested progenitor B cell lines, joining of RAG-generated DSBs in Ku70-deficient and Ku70/Lig4 double-deficient lines occurs through a translocation-like A-EJ mechanism. Thus, in G1-arrested, Lig4-deficient progenitor B cells are functionally end-joining suppressed due to Ku-dependent blockage of A-EJ, potentially in association with G1-phase down-regulation of Lig1. Finally, we suggest that differential impacts of Ku deficiency versus Lig4 deficiency on V(D)J recombination, neuronal apoptosis, and embryonic development results from Ku-mediated inhibition of A-EJ in the G1 cell cycle phase in Lig4-deficient developing lymphocyte and neuronal cells.","journal":"Proceedings of the National Academy of Sciences","year":2021,"id":165762,"datarank":0.5375278407684165,"base_score":3.58351893845611,"endowment":3.58351893845611,"self_citation_contribution":0.5375278407684165,"citation_network_contribution":0.0,"self_endowment_contribution":0.5375278407684165,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":35,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9595,"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":135572,"name":"Vipul Kumar","orcid":null,"position":1,"is_corresponding":false},{"id":689711,"name":"Marie Le Bouteiller","orcid":"0000-0002-4149-8488","position":2,"is_corresponding":false},{"id":690264,"name":"Jeffrey Zurita","orcid":null,"position":3,"is_corresponding":false},{"id":626396,"name":"Josefin Kenrick","orcid":"0000-0002-0110-5192","position":4,"is_corresponding":false},{"id":554146,"name":"Sherry Lin","orcid":"0000-0002-1275-8391","position":5,"is_corresponding":false},{"id":555064,"name":"Jiangman Lou","orcid":null,"position":6,"is_corresponding":false},{"id":238916,"name":"Jianqiao Hu","orcid":null,"position":7,"is_corresponding":false},{"id":33696,"name":"Adam Yongxin Ye","orcid":"0000-0002-1542-0740","position":8,"is_corresponding":false},{"id":689712,"name":"Cristian Boboilă","orcid":"0000-0003-4633-0366","position":9,"is_corresponding":false},{"id":271435,"name":"Frederick W. Alt","orcid":"0000-0002-0583-1271","position":10,"is_corresponding":false},{"id":626395,"name":"Richard L. Frock","orcid":"0000-0001-6963-4931","position":11,"is_corresponding":false},{"id":689710,"name":"Zhuoyi Liang","orcid":"0000-0003-1622-524X","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:45:40.838485Z","pmid":"34006647","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":[]}