{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T08:17:24Z","timestamp":1791274644011,"version":"4.1.0"},"reference-count":32,"publisher":"National Academy of Sciences","issue":"15","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2007,4,10]]},"abstract":"<jats:p>\n                    The ATM (ataxia telangiectasia mutated) protein plays a central role in sensing and responding to DNA double-strand breaks. Lymphoid cells are unique in undergoing physiologic double-strand breaks in the processes of Ig class switch recombination and T or B cell receptor V(D)J recombination, and a role for ATM in these processes has been suggested by clinical observations in ataxia telangiectasia patients as well as in engineered mice with mutations in the\n                    <jats:italic>Atm<\/jats:italic>\n                    gene. We demonstrate here a defect in thymocyte maturation in ATM-deficient mice that is associated with decreased efficiency in V-J rearrangement of the endogenous T cell receptor (TCR)\u03b1 locus, accompanied by increased frequency of unresolved TCR J\u03b1 coding end breaks. We also demonstrate that a functionally rearranged TCR\u03b1\u03b2 transgene is sufficient to restore thymocyte maturation, whereas increased thymocyte survival by bcl-2 cannot improve TCR\u03b1 recombination and T cell development. These data indicate a direct role for ATM in TCR gene recombination\n                    <jats:italic>in vivo<\/jats:italic>\n                    that is critical for surface TCR expression in CD4\n                    <jats:sup>+<\/jats:sup>\n                    CD8\n                    <jats:sup>+<\/jats:sup>\n                    cells and for efficient thymocyte selection. We propose a unified model for the two major clinical characteristics of ATM deficiency, defective T cell maturation and increased genomic instability, frequently affecting the TCR\u03b1 locus. In the absence of ATM, delayed TCR\u03b1 coding joint formation results both in a reduction of \u03b1\u03b2 TCR-expressing immature cells, leading to inefficient thymocyte selection, and in accumulation of unstable open chromosomal DNA breaks, predisposing to TCR\u03b1 locus-associated chromosomal abnormalities.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0611222104","type":"journal-article","created":{"date-parts":[[2007,4,3]],"date-time":"2007-04-03T23:57:16Z","timestamp":1175644636000},"page":"6323-6328","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":63,"title":["ATM deficiency impairs thymocyte maturation because of defective resolution of T cell receptor \u03b1 locus coding end breaks"],"prefix":"10.1073","volume":"104","author":[{"given":"Melanie S.","family":"Vacchio","sequence":"first","affiliation":[{"name":"*Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandru","family":"Olaru","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ferenc","family":"Livak","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J.","family":"Hodes","sequence":"additional","affiliation":[{"name":"*Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2007,4,10]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/35043058"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1011"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature01368"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1101\/sqb.2005.70.002"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature05112"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.0105-2896.2006.00361.x"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20041074"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20041162"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V96.5.1940.h8001940_1940_1946"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.12.6664"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.22.9.3174-3177.2002"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.956902"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04866"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80086-0"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.7.3336"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.2120773"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.15.1.433"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/333742a0"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(92)90453-J"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmbi.1996.0834"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.164.1.345"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.194.4.471"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0505564102"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni791"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.192.6.891"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-05-020917"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.172.2.409"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.15.1.177"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20021429"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200424918"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.7.4199"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.16.2.609"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.0611222104","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T15:09:26Z","timestamp":1649776166000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.0611222104"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,4,10]]},"references-count":32,"journal-issue":{"issue":"15","published-print":{"date-parts":[[2007,4,10]]}},"alternative-id":["10.1073\/pnas.0611222104"],"URL":"https:\/\/doi.org\/10.1073\/pnas.0611222104","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.1080839.533765","asserted-by":"object"}]},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,4,10]]},"assertion":[{"value":"2006-12-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2007-04-10","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}