{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T18:39:20Z","timestamp":1791311960614,"version":"4.3.1"},"reference-count":36,"publisher":"National Academy of Sciences","issue":"10","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,3,6]]},"abstract":"<jats:p>\n                    Nonhomologous end joining (NHEJ), a major pathway of DNA double-strand break (DSB) repair, is required during lymphocyte development to resolve the programmed DSBs generated during Variable, Diverse, and Joining [V(D)J] recombination. XRCC4-like factor (XLF) (also called Cernunnos or NHEJ1) is a unique component of the NHEJ pathway. Although germ-line mutations of other NHEJ factors abrogate lymphocyte development and lead to severe combined immunodeficiency (SCID), XLF mutations cause a progressive lymphocytopenia that is generally less severe than SCID. Accordingly, XLF-deficient murine lymphocytes show no measurable defects in V(D)J recombination. We reported earlier that ATM kinase and its substrate histone H2AX are both essential for V(D)J recombination in XLF-deficient lymphocytes, despite moderate role in V(D)J recombination in WT cells. p53-binding protein 1 (53BP1) is another substrate of ATM. 53BP1 deficiency led to small reduction of peripheral lymphocyte number by compromising both synapse and end-joining at modest level during V(D)J recombination. Here, we report that 53BP1\/XLF double deficiency blocks lymphocyte development at early progenitor stages, owing to severe defects in end joining during chromosomal V(D)J recombination. The unrepaired DNA ends are rapidly degraded in 53BP1\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    XLF\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    cells, as reported for H2AX\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    XLF\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    cells, revealing an end protection role for 53BP1 reminiscent of H2AX. In contrast to the early embryonic lethality of H2AX\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    XLF\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice, 53BP1\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    XLF\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice are born alive and develop thymic lymphomas with translocations involving the T-cell receptor loci. Together, our findings identify a unique function for 53BP1 in end-joining and tumor suppression.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1120160109","type":"journal-article","created":{"date-parts":[[2012,2,21]],"date-time":"2012-02-21T22:21:16Z","timestamp":1329862876000},"page":"3903-3908","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":90,"title":["Overlapping functions between XLF repair protein and 53BP1 DNA damage response factor in end joining and lymphocyte development"],"prefix":"10.1073","volume":"109","author":[{"given":"Xiangyu","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pathology and Cell Biology and Department of Pediatrics, Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, NY 10032; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxia","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cell Biology and Department of Pediatrics, Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, NY 10032; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard L.","family":"Dubois","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cell Biology and Department of Pediatrics, Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, NY 10032; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenta","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cell Biology and Department of Pediatrics, Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, NY 10032; and"},{"name":"Graduate program of Pathobiology and Molecular Medicine, College of Physicians and Surgeons, Columbia University, New York, NY 10032"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary","family":"Wolner","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cell Biology and Department of Pediatrics, Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, NY 10032; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shan","family":"Zha","sequence":"additional","affiliation":[{"name":"Department of Pathology and Cell Biology and Department of Pediatrics, Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, NY 10032; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2012,2,21]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.0105-2896.2004.00165.x"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.052308.093131"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.12.031"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.12.030"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601942"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2007.10.024"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2008.07.017"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0437964100"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0611734104"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09604"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2514"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07392"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04866"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80086-0"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.7.3336"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09585"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1013295108"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1019293108"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2009.04.025"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature07476"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20100244"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1004"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2010.09.010"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.str.2004.06.014"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.959202"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2011.03.019"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/76950"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.02.020"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80318-0"},{"key":"e_1_3_3_30_2","doi-asserted-by":"crossref","unstructured":"KP Lam R Kuhn K Rajewsky In vivo ablation of surface immunoglobulin on mature B cells by inducible gene targeting results in rapid cell death. Cell 90:1073\u20131083. (1997).","DOI":"10.1016\/S0092-8674(00)80373-6"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.19.8661"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.23.7.2556-2563.2003"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature09658"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2004.12.007"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.03.012"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20100285"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1120160109","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T21:14:57Z","timestamp":1649798097000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1120160109"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,2,21]]},"references-count":36,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2012,3,6]]}},"alternative-id":["10.1073\/pnas.1120160109"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1120160109","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,2,21]]},"assertion":[{"value":"2012-02-21","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}