{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T16:02:13Z","timestamp":1785859333554,"version":"3.56.0"},"reference-count":53,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2014,2,1]],"date-time":"2014-02-01T00:00:00Z","timestamp":1391212800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,2,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The RAG proteins are comprised of core endonuclease domains and noncore regions that modulate endonuclease activity. Mutation or deletion of noncore RAG regions in humans causes immunodeficiency and altered TCR repertoire, and mice expressing core but not full-length Rag1 (Rag1C\/C) or Rag2 (Rag2C\/C) exhibit lymphopenia, reflecting impaired V(D)J recombination and lymphocyte development. Rag1C\/C mice display reduced D-to-J and V-to-DJ rearrangements of TCR\u03b2 and IgH loci, whereas Rag2C\/C mice show decreased V-to-DJ rearrangements and altered V\u03b2\/VH repertoire. Because V\u03b2s\/VHs only recombine to DJ complexes, the Rag1C\/C phenotype could reflect roles for noncore RAG1 regions in promoting recombination during only the D-to-J step or during both steps. In this study, we demonstrate that a preassembled TCR\u03b2 gene, but not a preassembled D\u03b2J\u03b2 complex or the prosurvival BCL2 protein, completely rescues \u03b1\u03b2 T cell development in Rag1C\/C mice. We find that Rag1C\/C mice exhibit altered V\u03b2 utilization in V\u03b2-to-DJ\u03b2 rearrangements, increased usage of 3\u2032J\u03b1 gene segments in V\u03b1-to-J\u03b1 rearrangements, and abnormal changes in V\u03b2 repertoire during \u03b1\u03b2 TCR selection. Inefficient V\u03b2\/VH recombination signal sequences (RSSs) have been hypothesized to cause impaired V-to-DJ recombination on the background of a defective recombinase as in core-Rag mice. We show that replacement of the V\u03b214 RSS with a more efficient RSS increases V\u03b214 recombination and rescues \u03b1\u03b2 T cell development in Rag1C\/C mice. Our data indicate that noncore RAG1 regions establish a diverse TCR repertoire by overcoming V\u03b2 RSS inefficiency to promote V\u03b2 recombination and \u03b1\u03b2 T cell development, and by modulating TCR\u03b2 and TCR\u03b1 gene segment utilization.<\/jats:p>","DOI":"10.4049\/jimmunol.1301599","type":"journal-article","created":{"date-parts":[[2014,1,11]],"date-time":"2014-01-11T04:11:33Z","timestamp":1389413493000},"page":"1609-1619","source":"Crossref","is-referenced-by-count":12,"title":["Noncore RAG1 Regions Promote V\u03b2 Rearrangements and \u03b1\u03b2 T Cell Development by Overcoming Inherent Inefficiency of V\u03b2 Recombination Signal Sequences"],"prefix":"10.1093","volume":"192","author":[{"given":"Julie E","family":"Horowitz","sequence":"first","affiliation":[{"name":"Division of Cancer Pathobiology, Department of Pathology and Laboratory Medicine, Center for Childhood Cancer Research, Children\u2019s Hospital of Philadelphia, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, PA 19104; and , Philadelphia, PA 19104"},{"name":"Immunology Graduate Group, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, PA 19104; and , Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig H","family":"Bassing","sequence":"additional","affiliation":[{"name":"Division of Cancer Pathobiology, Department of Pathology and Laboratory Medicine, Center for Childhood Cancer Research, Children\u2019s Hospital of Philadelphia, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, PA 19104; and , Philadelphia, PA 19104"},{"name":"Immunology Graduate Group, Perelman School of Medicine at the University of Pennsylvania , Philadelphia, PA 19104; and , Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,2,15]]},"reference":[{"key":"2025032404131246500_r1","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1385\/IR:23:1:23","article-title":"RAG1 and RAG2 in V(D)J recombination and transposition","volume":"23","author":"Fugmann","year":"2001","journal-title":"Immunol. 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