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Using chemical and genetic approaches, we systematically evaluate potential A-EJ factors and DNA damage response (DDR) genes to support this mechanism by mapping the repair fates of RAG1\/2-initiated double-strand breaks in the context of Ig\u03ba locus V-J recombination and chromosome translocation. Our findings highlight a polymerase theta\u2013independent Parp1-XRCC1\/LigIII axis as central A-EJ components, supported by 53BP1 in the context of an Ataxia-telangiectasia mutated (ATM)\u2013activated DDR. Mechanistically, we demonstrate varied changes in short-range resection, MMEJ, and translocation, imposed by compromising specific DDR activities, which include polymerase alpha, Ataxia-telangiectasia and Rad3-related (ATR), DNA2, and Mre11. This study advances our understanding of DNA damage repair within the 53BP1 regulatory domain and the RAG1\/2 postcleavage complex.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.adn4682","type":"journal-article","created":{"date-parts":[[2024,7,31]],"date-time":"2024-07-31T14:12:36Z","timestamp":1722435156000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":10,"title":["ATM and 53BP1 regulate alternative end joining\u2013mediated V(D)J recombination"],"prefix":"10.1126","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0125-8201","authenticated-orcid":true,"given":"Jinglong","family":"Wang","sequence":"first","affiliation":[{"name":"Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA 94305, 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